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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND# t  e. O9 s: s0 X
GONADOTROPIN
- y' Z) P* s8 @3 W! JRICHARD C. KLUGO* AND JOSEPH C. CERNY9 r: W) P( K8 w: y
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
) L9 O# K. \; Y' ]ABSTRACT
$ Q8 \& O6 U5 Q' `% r' f0 sFive patients were treated with gonadotropin and topical testosterone for micropenis associated7 P5 ?( h+ J* Q2 f7 _# I( K
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-: o/ n, [5 ?/ y
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
$ ]! Y' x0 G) `  i  G1 ^% f+ L1 @- g3 tcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
6 E5 a( Z. J/ m, T! Q6 k' R# M% {for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent# l2 w  L0 h# {5 z
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
) ^! L1 F- O0 p. gincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response; S* L6 E1 [8 D/ ^5 q: `
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
: J' G! E& d% C$ O- e. Z) Jstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile+ b1 t7 S# F& c9 e" X2 V% ^, @
growth. The response appears to be greater in younger children, which is consistent with previ-
) O8 w- _& o8 lously published studies of age-related 5 reductase activity.  {9 x2 d& G$ ]: f* p
Children with microphallus regardless of its etiology will" V5 z9 |, W7 K; }1 p0 F% {6 j6 f/ `
require augmentation or consideration for alteration of exter-4 d) i% A8 [! g; x2 a
nal genitalia. In many instances urethroplasty for hypo-7 D& y) N* K5 R5 @: I
spadias is easier with previous stimulation of phallic growth.
: a2 c2 c) r, pThe use of testosterone administered parenterally or topically
0 v5 ^, m5 Z) K5 thas produced effective phallic growth. 1- 3 The mechanism of
9 ], T: g% K8 ]1 fresponse has been considered as local or systemic. With this4 x3 D" s+ j8 j6 N
in mind we studied 5 children with microphallus for response
6 P* |8 N/ k$ P" a) \to gonadotropin and to topical testosterone independently.& s( K, |# u; R- B
MATERIALS AND METHODS- a$ a+ ]  r; k; P4 V* U; s) D) r) E- h
Five 46 XY male subjects between 3 and 17 years old were% r8 u( R8 a. `' k; a9 z
evaluated for serum testosterone levels and hypothalamic
# G7 J4 c* w6 ~6 lfunction. Of these 5 boys 2 were considered to have Kallmann's
# c& ]9 U  Q! a/ I4 fsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
" O! F8 U& m1 k9 K4 I9 G2 `lamic deficiency. After evaluation of response to luteinizing, u$ z$ j& e) O
hormone-releasing hormone these patients were treated with
% h" n4 W) F5 s1 @( E5 t" N1,000 units of gonadotropin weekly for 3 weeks. Six weeks
# x/ [6 n1 ^- M, P( L# Tafter completion of gonadotropin therapy 10 per cent topical
$ c$ q9 ^0 d3 p; wtestosterone was applied to the phallus twice daily for 3 weeks.. J+ A/ ~9 h3 O8 U0 X
Serum testosterone, luteinizing hormone and follicle-stimulat-
1 i' z3 f* {1 Qing hormone were monitored before, during and after comple-
9 S$ Y/ J/ S9 W7 Ytion of each phase of therapy. Penile stretch length was4 `+ r# {6 v, h
obtained by measuring from the symphysis pubis to the tip of7 P) ^& t* X2 E3 \" i1 T
the glans. Penile circumferential (girth) measurements were
+ k4 t3 _- ^# }3 o! |& P2 K$ ~obtained using an orthopedic digital measuring device (see, x2 z$ W) x/ U6 a+ W8 {2 J
figure).9 B  p2 @0 U% J. X5 L5 q6 _
RESULTS: i8 G* W3 o0 X1 h& G
Serum testosterone increased moderately to levels between- |7 w( q& E" b" r
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# v2 N( f+ w" w; e; q" h5 Gterone levels with topical testosterone remained near pre-
- O) O. o7 e1 _: y0 Otreatment levels (35 ng./dl.) or were elevated to similar levels
' Z' ]* Z" j3 j/ b; j* Mdeveloped after gonadotropin therapy (96 ng./dl.). Higher9 G  s( b7 d1 a9 [: C
serum levels were noted in older patients (12 and 17 years old),. |1 {3 Y; D3 N' l$ v
while lower levels persisted in younger patients (4, 8, and 10: j' `( b+ H. t; ?! m! F
years old) (see table). Despite absence of profound alterations* _0 g# t# r! A3 ?
of serum testosterone the topical therapy provided a greater3 d  a1 v2 X3 n( G
Accepted for publication July 1, 1977. ·
. u& J+ a" C2 f) X% x' z+ dRead at annual meeting of American Urological Association,+ K6 o) k; ~* Z/ \5 J+ l2 s
Chicago, Illinois, April 24-28, 1977.3 f9 \9 b, l0 R: R
* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 f4 D4 s0 z- X5 |  A. a/ w2799 W. Grand Blvd., Detroit, Michigan 48202.
2 S# h4 r% b) R$ \2 {+ Pimprovement in phallic growth compared to gonadotropin., p! Q9 `7 _: l# v$ l
Average phallic growth with gonadotropin was 14.3 per cent8 a1 f/ p0 c2 ~: l
increase in length and 5.0 per cent increase of girth. Topical( Z2 x2 P) q# A; x9 o
testosterone produced a 60.0 per cent increase of phallic length
3 {% V& T; a$ F0 k, _and 52.9 per cent increase of girth (circumference). The
/ ?# K6 V+ D, Q5 u7 e5 vresponse to topical testosterone was greatest in children be-
& {+ y' b7 o1 k0 p( t8 ltween 4 and 8 years old, with a gradual decrease to age 17
4 |# [/ z+ A; j) A) _years (see table).
# O1 I: _2 x$ U; O7 e& bDISCUSSION% x1 E3 D1 O2 n: O5 c
Topical testosterone has been used effectively by other  i9 j, d* Q0 x* e) Z
clinicians but its mode of action remains controversial. Im-
  @8 @( Z" g7 d9 gmergut and associates reported an excellent growth response( f5 S0 d7 S: H* R6 d) W# q
to topical testosterone with low levels of serum testosterone,
+ J  G! q+ X+ F* s; b' isuggesting a local effect.1 Others have obtained growth re-# I$ ?0 ~$ N& [# ~! t- ^
sponse with high. levels of serum testosterone after topical
4 W2 i) e: ^* _+ Z# _0 L( F* Ladministration, suggesting a systemic response. 3 The use of
* U# i0 M1 S3 ~2 z# |1 Rgonadotropin to obtain levels of serum testosterone compara-1 a9 ^" p; F9 P# t
ble to levels obtained with topical testosterone would seem to
9 m& _" e' j# D  \! Qprovide a means to compare the relative effectiveness of
  x% `) v* S& T8 s3 qtopical testosterone to systemic testosterone effect. It cer-6 d( V. `" G* H' ?5 o1 n
tainly has been established that gonadotropin as well as par-
1 F: {3 u6 u; Z; ?% T- Zenteral testosterone administration will produce genital
1 w* o4 z+ P( J% ^  \! qgrowth. Our report shows that the growth of the phallus was. F6 c- p& H; c1 U
significantly greater with topical applications than with go-% t- c  [+ u) ?! |0 U
nadotropin, particularly in children less than 10 years old.
$ R& B8 i! D. m6 C- ?The levels of serum testosterone remained similar or lower
0 m- m- H0 A% ^; W, w3 `1 @2 dthan with gonadotropin during therapy, suggesting that topi-
. G# M( A: a- h" E+ }8 l; jcal application produces genital growth by its local effect as
( T( M) q- ^8 ]8 [well as its systemic effect.+ {9 s$ p* E6 ^, q3 E
Review of our patients and their growth response related to
- \5 H% X* d- m1 a, f' `age shows a greater growth response at an earlier age. This is- o, z* ^# g; p& q7 ^, t0 {* d  a
consistent with the findings of Wilson and Walker, who: a# G% i) R' R, F! g, C
reported an increased conversion of testosterone to dihydrotes-
) I" C! A5 v! G1 I+ rtosterone in the foreskin of neonates and infants.4 This activ-' e/ q  u) x* K
ity gradually decreases with age until puberty when it ap-8 ]& @2 [. X* u. w. E% J
proaches the same level of activity as peripheral skin. It may* O; n4 z( U% b- s4 G& T
well be that absorption of testosterone is less when applied at
% K4 i9 w; T; P3 z" z; \an earlier age as suggested by lower serum levels in children
. }  X6 I0 r: B" j  `9 Nless than 10 years old. This fact may be explained by the
% }2 p9 _* `" T2 G5 k3 fgreater ability of phallic skin to convert testosterone to dihy-
1 q9 Q/ N( h3 Y" f+ Cdrotestosterone at this age. Conversely, serum levels in older
: G1 W- c- G6 Cpatients were higher, possibly because of decreased local
! U" O( R9 m8 v9 D  Y* p667
1 }& j$ a6 [4 Q- a+ _' ?668 KLUGO AND CERNY, Y; h- ~8 }1 _7 `8 \5 D. z
Pt. Age$ ^$ w  U& Z- I
(yrs.)
; P% }4 T3 e! h  Y% C" \+ XSerum Testosterone Phallus (cm.) Change Length
2 [  ~# u2 y+ Z' i' J) c(ng./dl.) Girth x Length (%)" G" [- h5 @* @% U! s7 {4 p: X1 o
4
5 M" S# V4 j8 @0 k2 }8
3 q( [3 n! ], B5 U) ]4 J. g8 x( X10
) @9 K1 H; t/ V# m% U12. v5 ]+ o  E2 V) i# u" O% \. Z
170 U- r9 s8 c' K' h2 S* C( x- m
Gonadotropin
0 q& F' D. L1 R' `71.6 2.0 X 3 16.6) Q8 T3 f4 ]  [3 m0 X; ~
50.4 4.0 X 5.0 20.0( y% t  @; c# }: i
22.0 4.5 X 4.0 25.0
+ F7 u  h/ i7 ~5 A84.6 4.0 X 4.5 11.1
/ D1 F$ G% R# b% D6 y8 s85.9 4.5 X 5.5 9.07 h# l+ q& ~1 [1 Y, p
Av. 14.3
3 P+ ?* D, t8 I" `/ c5 \6 y: A4
# g' Q) ~1 J% r1 I# Y8
, _9 z& i" K' p0 X% ^* ?# I: {10
) U- Q- s4 t: N( x  u0 ~12
, n, l& y: |* g% [3 T" ]; O17. M: |5 A% d" C  }
Topical testosterone2 w0 [1 \0 ?8 I
34.6 4.5 X 6.5 85
) N/ u: z, B, Q7 }1 ?38.8 6.0 X 8.5 70
! w* q" P3 w6 e& @  L( M' ^% u40.0 6.0 X 6.5 62.52 \$ j5 R. Q1 C# f7 j- N
93.6 6.0 X 7.0 55.5- T& J$ }- v% N* T' N
95.0 6.5 X 7.0 27.2, K' G! h: d+ {# z
Av. 60.0
2 U/ y, v2 d# j! xavailable testosterone. Again, emphasis should be placed on
$ d$ y- y' @4 Y' k+ cearly therapy when lower levels of testosterone appear to
" Q9 d  {# G; X! J9 R, @provide the best responses. The earlier therapy is instituted
8 c7 {' j2 I/ V, y' Q) r! zthe more likely there will be an excellent response with low# |+ e, g0 J  u6 n. j
serum levels. Response occurs throughout adolescence as4 G, e0 C! w' c0 D9 u
noted in nomograms of phallic growth. 7 The actual response
) B3 c8 x+ P5 z2 xto a given serum level of testosterone is much greater at birth
" Q* f6 e) k2 band gradually decreases as boys reach puberty. This is most
4 M) P9 ^! Y# ]6 `% I* b3 klikely related to the conversion of testosterone to dihydrotes-
) @3 d9 r- X- btosterone and correlates well with the studies of testosterone5 X9 M9 v8 U: f( L& I( Q
conversion in foreskin at various ages.
6 ]/ N8 D9 }% MThe question arises regarding early treatment as to whether
; `) F9 j$ @/ D. ~+ |. ^. b. ~8 vone might sacrifice ultimate potential growth as with acceler-+ E* W0 X/ g# E$ Q" Y
ated bone growth. The situation appears quite the reverse
& H4 T$ y- ~9 P1 p& j: @with phallic response. If the early growth period is not used
0 ]: M; T( t+ j, I. uwhen 5a reductase activity is greatest then potential growth
2 W0 i/ ^( @) B* a7 [! h5 |4 [may be lost. We have not observed any regression of growth4 @! A6 k3 i: y# M' `0 J- T
attained with topical or gonadotropin therapy. It may well/ t9 r4 K. D. g6 ?
be that some patients will show little or no response to any0 i) B& @; M9 v3 F! z
form of therapy. This would suggest a defect in the ability to; d# g6 a% d+ z1 n$ o: J. j- K
convert testosterone to dihydrotestosterone and indicate that5 A, f7 ^% F. e  H3 a
phallic and peripheral skin, and subcutaneous tissue should
/ T$ K5 z& v; D# Pbe compared for 5a reductase activity.
6 P% n& V- ]- m+ l$ c2 fA, loop enlarges to measure penile girth in millimeters. B,
' K- J' \  R# Dexample of penile girth computed easily and accurately.
! }, B( G8 y% t2 jconversion of testosterone to dihydrotestosterone. It is in this: U( y" P; s% D3 R5 J% P* L: L0 \
older group that others have noted high levels of serum; A8 ^$ d: t" B% A4 m$ \0 `. ?9 C
testosterone with topical application. It would also appear
& o: q, ?/ g1 s' {( Xthat phallic response during puberty is related directly to the# d: t) w. L( D. P* v: I
serum testosterone level. There also is other evidence of local
& E( |! c2 @; }response to testosterone with hair growth and with spermato-
+ o  b. M/ J5 g; wgenesis. 5• 6
) |0 R7 d+ N+ E7 E  o; {Administration of larger doses of gonadotropin or systemic# B) F! h2 J, Y8 E
testosterone, as well as topical applications that produce
/ b# J& }' o4 C  whigher levels of serum testosterone (150 to 900 ng./dl.), will
2 Q0 ?( x: W1 g" j# X0 T1 _also produce phallic growth but risks accelerated skeletal. n& Z4 m- l3 |5 C
maturation even after stopping treatment. It would appear2 m3 `6 ?, H! ~/ O
that this may be avoided by topical applications of testosterone
8 P7 Q* u7 k- Land monitoring of serum testosterone. Even with this control
) x) E1 W! u. i5 F$ X  ^) Bthe duration of our therapy did not exceed 3 weeks at any$ E/ m9 S; \8 ^- L2 T8 t) F
time. It is apparent that the prepuberal male subject may( c8 ?( _- h$ F
suffer accelerated bone growth with testosterone levels near
& c" `: H7 m. g, m  U/ \1 }  l200 ng./dl. When skeletal maturation is complete the level of
/ E1 u+ U! f) |* V( ]serum testosterone can be maintained in the 700 to 1,300 ng./5 c" n6 k  V  L/ w" N
dl. range to stimulate phallic growth and secondary sexual) q( T# g* Q6 V# ]; q" Y
changes. Therefore, after skeletal maturation parenteral tes-
# H3 T6 }+ Z3 s/ q" ptosterone may be used to advantage. Before skeletal matura-' ~) B; S9 x  b% Y& \9 ?
tion care must be taken to avoid maintaining levels of serum5 q5 S9 P+ T5 O9 |
testosterone more than 100 ng./dl. Low-dose gonadotropin
0 M2 e- L% M  Z1 I1 Rdepends upon intrinsic testicular activity and may require
2 l/ X6 _4 l6 W" [prolonged administration for any response.2 k. \! e1 E7 _% A4 }! ^
Alternately, topical testosterone does not depend upon tes-
- S3 r- j2 @) f- u' Bticular function and may provide a more constant level of2 N: O( s4 m% u4 ], e: }& q( V
REFERENCES
4 I. P9 W/ B* h* s- f# Y6 A. g1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,* j9 f5 M3 T- F1 |3 ^! T6 `
R.: The local application of testosterone cream to the prepub-
9 O' ~4 v2 l- t8 Hertal phallus. J. Urol., 105: 905, 1971.
7 p% t0 ?8 G" D' i0 i6 A2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) Z, [1 k( `8 o% |% I: b. @treatment for micropenis during early childhood. J. Pediat.,  W2 V: A7 Q& M  x2 S: P' `) Z
83: 247, 1973., n. F, U& H& X
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
+ s) O& `& @/ F, Z. vone therapy for penile growth. Urology, 6: 708, 1975.2 J  Z8 R& X: I6 l
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) H3 o7 [2 W2 l
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 K2 P1 ]' Y7 y6 a
skin slices of man. J. Clin. Invest., 48: 371, 1969.
. p& H8 A! z0 s/ [3 ~$ A/ ]5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
/ o- `2 T9 K! a, q* W/ q6 Z1 }# Mby topical application of androgens. J.A.M.A., 191: 521, 1965.
8 {  H6 Z6 \1 M0 k  d. v; a2 C6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local5 c) T3 p) J8 ^4 ~0 o
androgenic effect of interstitial cell tumor of the testis. J.
% T6 H9 s: ^3 F: ?Urol., 104: 774, 1970.
( a/ G. m0 g& ]1 H* [7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-8 ]) e- s6 A0 d/ K8 X  H
tion in the male genitalia from birth to maturity. J. Urol., 48:
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