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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND) j5 m( z: e( H5 R8 `# ]# ?
GONADOTROPIN- U* v  K  ^; e) p) K8 r7 i
RICHARD C. KLUGO* AND JOSEPH C. CERNY/ z5 \  K; j6 p
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan% l" }5 ?" x& U4 n3 W8 G& z
ABSTRACT
/ D7 V4 W: T, {/ A% DFive patients were treated with gonadotropin and topical testosterone for micropenis associated
' g4 O) d' d8 ?9 P0 V( b5 `with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-& A5 r0 S& c4 }+ \' O* e
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone1 m5 q7 F6 I6 t$ N. A/ {
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent0 c! X0 b  E$ v. {0 b3 F* x# Q
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 q% D1 R, t+ s+ p5 k. ^increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 R2 E+ a& K! ?$ M3 p5 X' d* Pincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response. \# L7 `. |+ q3 I1 A6 G& U
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
' x+ N+ R. v: Y0 k3 tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
( b  u* f. ]) m" w- y0 zgrowth. The response appears to be greater in younger children, which is consistent with previ-
7 k0 u7 ]5 J4 P* s" \. U4 t- Iously published studies of age-related 5 reductase activity.9 M- a- Q4 g, r2 l% B! X- Z
Children with microphallus regardless of its etiology will
: H$ P* U( ~8 R0 ~: D6 N( wrequire augmentation or consideration for alteration of exter-, k0 t# {; z* T' M: x; D
nal genitalia. In many instances urethroplasty for hypo-
: U- l# s  S  I0 c0 I  n' G2 w1 G& h+ u0 Jspadias is easier with previous stimulation of phallic growth.: m8 ?4 r* F- s, P- u+ A
The use of testosterone administered parenterally or topically
& ~8 g  t# P" i# {! p) Rhas produced effective phallic growth. 1- 3 The mechanism of: R! |' p5 H- m
response has been considered as local or systemic. With this
5 g: E# y1 r  O* R1 W' d0 fin mind we studied 5 children with microphallus for response! y* Q* h1 v: a* C
to gonadotropin and to topical testosterone independently.
2 b: l) Q( o/ q. l# A6 m& y! ~MATERIALS AND METHODS3 t# i! O2 y, X# `" x2 i1 d
Five 46 XY male subjects between 3 and 17 years old were/ Z' F; `' \. m9 O
evaluated for serum testosterone levels and hypothalamic
( @, Z, Z/ G  R0 Q& {$ K! {& Tfunction. Of these 5 boys 2 were considered to have Kallmann's
( T$ f# H- f) d: x/ S8 \) R- k. Csyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-! m1 J3 f2 \) k
lamic deficiency. After evaluation of response to luteinizing6 N) C' J2 F( F  J. B( l
hormone-releasing hormone these patients were treated with: J5 }3 s4 O; o& a
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
0 l( N! f1 W6 ~& jafter completion of gonadotropin therapy 10 per cent topical
1 b! z6 l5 k$ [3 ]+ @testosterone was applied to the phallus twice daily for 3 weeks.: b# U1 g. L" m! T
Serum testosterone, luteinizing hormone and follicle-stimulat-
1 I% v8 j. C/ U. a4 g8 eing hormone were monitored before, during and after comple-' ^1 S: z% c: ?4 _  C  A# ^. K
tion of each phase of therapy. Penile stretch length was( J, q' U( \0 q7 F* D
obtained by measuring from the symphysis pubis to the tip of3 h7 \" I) R* k- M% J+ g
the glans. Penile circumferential (girth) measurements were
* ^+ z& N6 e3 ?8 [% Dobtained using an orthopedic digital measuring device (see/ c9 j! L6 a/ b! V4 b* s
figure).- V  `$ K8 u: G# |7 H
RESULTS' b; K% @0 e% h1 b! |
Serum testosterone increased moderately to levels between. `" D7 w7 \, d* z+ [! e6 E! ^
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-' J4 G  ?0 n# e( k/ t3 e
terone levels with topical testosterone remained near pre-0 g% |& a# Z: f' N/ y7 p
treatment levels (35 ng./dl.) or were elevated to similar levels2 b; U4 o, m3 H' z' V
developed after gonadotropin therapy (96 ng./dl.). Higher
7 S- `. P, ^( C& |serum levels were noted in older patients (12 and 17 years old),. {# [6 u6 a) }  z( z. x
while lower levels persisted in younger patients (4, 8, and 10
2 m; B+ n9 u4 @years old) (see table). Despite absence of profound alterations
; D. Z0 i# \/ O4 C/ aof serum testosterone the topical therapy provided a greater/ ]' `& \# d) Q) ?! ~
Accepted for publication July 1, 1977. ·9 V( C) d+ i9 n5 I# F9 d
Read at annual meeting of American Urological Association,
- I1 p9 L2 T* K! hChicago, Illinois, April 24-28, 1977.! t8 f' }/ s' I: d
* Requests for reprints: Division of Urology, Henry Ford Hospital,
  D4 O: p6 |3 l3 \# k( Q2 i$ X2799 W. Grand Blvd., Detroit, Michigan 48202.- Z3 u8 B% G8 j( ?$ P* U
improvement in phallic growth compared to gonadotropin.
$ c6 }; C2 Q+ L  V* I5 IAverage phallic growth with gonadotropin was 14.3 per cent
! [) }( L: f" ], q; P% nincrease in length and 5.0 per cent increase of girth. Topical; U: J* ]1 ?* v. m8 q& s# x8 t
testosterone produced a 60.0 per cent increase of phallic length
) ?4 ^6 {* ]" L1 m; H. V' p$ _and 52.9 per cent increase of girth (circumference). The
" f5 N' |0 r; D0 y) dresponse to topical testosterone was greatest in children be-( G! T6 k; d: H  ]6 z
tween 4 and 8 years old, with a gradual decrease to age 172 E9 V- w2 v1 `
years (see table).* S+ r0 D) \& B& F; c: t4 }2 r5 L
DISCUSSION
/ ~; X7 X, V3 m# jTopical testosterone has been used effectively by other
# h; }" B4 I/ m3 iclinicians but its mode of action remains controversial. Im-) `. D8 }" N* O! ~7 J7 _
mergut and associates reported an excellent growth response
' U, \3 `; q- M! J: i5 Dto topical testosterone with low levels of serum testosterone,9 Y3 d5 R; b# r# i1 h3 x* H
suggesting a local effect.1 Others have obtained growth re-1 T% c4 }! _8 g1 |
sponse with high. levels of serum testosterone after topical& T$ [6 l6 [3 [. s
administration, suggesting a systemic response. 3 The use of
8 T) P$ f& D; w, B6 ~gonadotropin to obtain levels of serum testosterone compara-* u% R  j' _/ P2 w
ble to levels obtained with topical testosterone would seem to- |' }) Y$ N3 m. w. E" K9 w' ~, ~8 K7 a
provide a means to compare the relative effectiveness of& Y$ B( y  k+ P8 ^% v) n
topical testosterone to systemic testosterone effect. It cer-
& C8 {; m+ c; h; P6 ytainly has been established that gonadotropin as well as par-! p8 j8 r. x% I5 C: K: d- ^; Q
enteral testosterone administration will produce genital9 o0 u/ e: M) p
growth. Our report shows that the growth of the phallus was+ u4 m" W7 n- ]- Z5 Z7 }1 Q
significantly greater with topical applications than with go-+ |& ]  t3 g0 ~+ ~) {& M7 B
nadotropin, particularly in children less than 10 years old.
' i* w- L8 H2 Z7 DThe levels of serum testosterone remained similar or lower
! ]2 H6 w7 |/ ^3 w4 V0 @; Y0 Pthan with gonadotropin during therapy, suggesting that topi-, _! e& a+ k7 q' N/ j
cal application produces genital growth by its local effect as' n1 b6 G4 E/ ^* [3 O# o
well as its systemic effect.! X1 w& z+ y4 a2 }
Review of our patients and their growth response related to; j2 Q& j4 F( K$ o$ x
age shows a greater growth response at an earlier age. This is+ K1 d  q$ I0 h- n/ t& S8 E
consistent with the findings of Wilson and Walker, who: ~8 l( m0 g1 }3 |1 \0 N
reported an increased conversion of testosterone to dihydrotes-& w$ d% H% i+ p, x% S
tosterone in the foreskin of neonates and infants.4 This activ-) ~! d& a/ L% N: N- a8 @
ity gradually decreases with age until puberty when it ap-% Y7 \2 R$ M. {- z/ \1 v
proaches the same level of activity as peripheral skin. It may" P6 A& ^' b  j  t+ |- _
well be that absorption of testosterone is less when applied at( g6 j" l6 ~6 I
an earlier age as suggested by lower serum levels in children9 \; {- Q0 Z! Q+ z% F
less than 10 years old. This fact may be explained by the
+ W/ p3 b7 Y+ j& y' d+ igreater ability of phallic skin to convert testosterone to dihy-
0 t% ]& i8 {& s* E; |5 Hdrotestosterone at this age. Conversely, serum levels in older+ g9 n* @5 Q4 J& b, E
patients were higher, possibly because of decreased local  F# B( S( Y' S+ a0 E9 u
667
* g4 i9 b) Z$ g, i668 KLUGO AND CERNY
- j# F% u" o( \' N1 ]! u( w$ f( EPt. Age
  Y' E7 {) b: \( Q4 z* R(yrs.)) w( }; Q, f" ~8 C' }3 A3 i
Serum Testosterone Phallus (cm.) Change Length
2 x2 Z" p, c) {; U(ng./dl.) Girth x Length (%)$ P0 k7 a; \. D, \# m
4, `9 y0 N" y8 F3 N% j( D
87 B# ?/ u: y$ J) I# q5 Z% L
10
! o8 [! f/ \. r) j; [" l- p2 X  B12# c9 r: S2 @1 Z5 {: m
17
! r; w8 R8 f* K1 {! W& qGonadotropin$ |, j" T0 h- G$ A% @1 I$ W
71.6 2.0 X 3 16.6
! ~4 |3 D# j6 t, j2 |50.4 4.0 X 5.0 20.07 R$ C; I) S) f2 m0 m
22.0 4.5 X 4.0 25.0, i: _9 M& x) h2 A
84.6 4.0 X 4.5 11.1
$ T0 ~- Q( ~. a85.9 4.5 X 5.5 9.0
, x1 [/ }9 e" I& j' Y" \! p/ ~' pAv. 14.3
- p6 U  |$ }# m  G+ F4
; F  h' f) X. c. _! V2 ^8
: o$ K3 G+ H( ^$ f0 D  |' o10
& i6 m! @# o6 I, s3 }12
/ {  h/ }1 F( m17
. {) d2 r3 {# n/ v7 q6 sTopical testosterone) i+ u" ~4 K6 {; I% k  f  o
34.6 4.5 X 6.5 85
1 ]; _* w9 T. v/ H38.8 6.0 X 8.5 70
4 W8 C8 R& {' T' l- P* ?' V( S40.0 6.0 X 6.5 62.5
) N% u: r* n6 H  e6 P93.6 6.0 X 7.0 55.53 A6 I  @9 }6 t: G
95.0 6.5 X 7.0 27.2* |7 ], z0 F# k0 h- ]9 a+ E$ U- H
Av. 60.0. G' g- o( Y+ ~9 E* P. N. E
available testosterone. Again, emphasis should be placed on0 h; I  u- P9 ]. L3 P' B
early therapy when lower levels of testosterone appear to
2 ]; C$ R2 c( G3 B- M3 G2 k5 t9 vprovide the best responses. The earlier therapy is instituted
( t3 d9 H) I9 I( z! ?0 Cthe more likely there will be an excellent response with low$ J) X) S( p) x; h4 M
serum levels. Response occurs throughout adolescence as
6 R9 x9 I) U7 n  W* G0 t) ]8 mnoted in nomograms of phallic growth. 7 The actual response
! N6 ~8 a0 K, Y0 i' q3 ^( l( h# kto a given serum level of testosterone is much greater at birth" x6 C( O8 x$ K1 M
and gradually decreases as boys reach puberty. This is most
, s0 I( j! w8 ^+ ^& @likely related to the conversion of testosterone to dihydrotes-( C8 t& K9 X6 w, T1 }% d2 o$ Q" t
tosterone and correlates well with the studies of testosterone8 D; e1 P/ w9 t- G6 W
conversion in foreskin at various ages.
: ]+ X1 I8 G  g% a$ ?3 U. DThe question arises regarding early treatment as to whether
2 \! `- N! ?% ?% w9 yone might sacrifice ultimate potential growth as with acceler-: d3 ~, l+ H( }9 s/ E. f* s
ated bone growth. The situation appears quite the reverse  s8 D! U9 G. ]1 m9 s2 K7 W. j$ A( U
with phallic response. If the early growth period is not used
+ S! k2 \# S% l& K0 Qwhen 5a reductase activity is greatest then potential growth
. a  P. m4 z" G9 k. H8 b: Kmay be lost. We have not observed any regression of growth
0 _- s* {$ K: b$ r! fattained with topical or gonadotropin therapy. It may well
4 m5 N8 C; @/ ^) Z- m! ebe that some patients will show little or no response to any
+ C) F6 X7 q- G* C% t* fform of therapy. This would suggest a defect in the ability to. n, ]4 a' G9 K! W) d$ p
convert testosterone to dihydrotestosterone and indicate that8 `7 F. x. V3 F4 `/ d/ R5 l% Z  d
phallic and peripheral skin, and subcutaneous tissue should
, i8 a5 O) l: X* p% sbe compared for 5a reductase activity.* w$ \! z8 M- ?7 ~) C
A, loop enlarges to measure penile girth in millimeters. B,4 L9 G2 z3 r: o! H: `7 _3 V3 y* y
example of penile girth computed easily and accurately.
2 w# q( D1 X! |$ n6 d& i' B0 {9 Y$ m6 Iconversion of testosterone to dihydrotestosterone. It is in this4 O1 l2 X2 Q9 w4 R) T& ^' n6 a1 d
older group that others have noted high levels of serum4 i! w; h, \! B# k3 Q+ \  \2 c6 T2 b8 p
testosterone with topical application. It would also appear  [* d7 N4 o0 c- y
that phallic response during puberty is related directly to the
! m6 K$ ]' F" r, v0 vserum testosterone level. There also is other evidence of local. `2 y3 n- b& t0 h
response to testosterone with hair growth and with spermato-
+ V) t5 {5 s1 z7 @% t. F' Ggenesis. 5• 6% @, s$ U, a) V' B! p
Administration of larger doses of gonadotropin or systemic2 l6 H% b6 l0 _0 _3 t
testosterone, as well as topical applications that produce
; W( o( c2 S- l: g% rhigher levels of serum testosterone (150 to 900 ng./dl.), will2 D& ~# y9 t$ y( m  ~+ W
also produce phallic growth but risks accelerated skeletal! `- \) P" w) t. s
maturation even after stopping treatment. It would appear
1 N/ v/ u5 Q6 j0 a) x& D) ]that this may be avoided by topical applications of testosterone
' F( f8 a" I0 d9 B# }and monitoring of serum testosterone. Even with this control: Q, R5 ?0 J3 P* N
the duration of our therapy did not exceed 3 weeks at any8 S  P, i9 z0 @+ u5 M# y8 q3 K
time. It is apparent that the prepuberal male subject may
& U; f3 E# ?7 K) U6 y  B; _suffer accelerated bone growth with testosterone levels near7 _+ P$ j0 c+ \" `) x) d. u
200 ng./dl. When skeletal maturation is complete the level of
' M0 g/ w  W" G2 oserum testosterone can be maintained in the 700 to 1,300 ng./: V6 o3 D- `7 b. G8 p+ @+ y% ^2 Q
dl. range to stimulate phallic growth and secondary sexual
; B* K6 C1 Q% z& R: A9 T6 P& v. ichanges. Therefore, after skeletal maturation parenteral tes-
4 T% s4 X9 u/ L$ V) ^( qtosterone may be used to advantage. Before skeletal matura-
, K. U& p  g/ G4 \0 ution care must be taken to avoid maintaining levels of serum
% ]4 X- V1 z0 F) }& A! ~testosterone more than 100 ng./dl. Low-dose gonadotropin) t& z5 P( S- |" ]: l
depends upon intrinsic testicular activity and may require
' \1 l  k. ]  U- a7 _( ?( h" Vprolonged administration for any response.
9 ?; W& o! {: D# l+ D/ iAlternately, topical testosterone does not depend upon tes-
5 i. T( X! f/ n6 w* L/ r+ gticular function and may provide a more constant level of
: S* P  U( {9 T& s- nREFERENCES
! N0 F6 e+ @& \! Y( C1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,4 P) R' W- _% \; p; y% S( X
R.: The local application of testosterone cream to the prepub-
) q+ x3 \7 @1 E1 Jertal phallus. J. Urol., 105: 905, 1971." `7 a" [0 A( U5 e, j' ]; j
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone! H1 S) d- j* x
treatment for micropenis during early childhood. J. Pediat.,$ a* \2 A5 g4 j/ w" \8 _8 q
83: 247, 1973.
/ V/ i5 ?3 L2 o# ~) }8 X$ o3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-5 F9 T1 @$ x- l" D7 S. m
one therapy for penile growth. Urology, 6: 708, 1975.
' v# U( W1 W8 q; c4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
5 z* E& w& T; V' R. uto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by! H4 p5 x, n" g5 E$ V. X
skin slices of man. J. Clin. Invest., 48: 371, 1969.9 `" H' `4 `! a1 e$ G
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth7 c8 ~: U, Q: l
by topical application of androgens. J.A.M.A., 191: 521, 1965.
+ o( B! L* M! M1 K3 G, a/ [6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
$ Z! {! d( C1 C% S& q5 j1 pandrogenic effect of interstitial cell tumor of the testis. J.+ _* H+ }$ s3 b$ W
Urol., 104: 774, 1970.
  C& T  g5 k# g$ ]7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-# k/ `9 G5 O: H
tion in the male genitalia from birth to maturity. J. Urol., 48:
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