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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND" P6 m6 ]% i: O; i# Z
GONADOTROPIN! S, P" u* i; Q; I7 [$ O  }
RICHARD C. KLUGO* AND JOSEPH C. CERNY
% [0 Z  b  @) W+ S; ~% e8 E2 pFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
% B* p9 `. z5 k( W- |. Q  ]ABSTRACT7 _1 N2 A# y8 ?, L
Five patients were treated with gonadotropin and topical testosterone for micropenis associated2 E$ ?7 c6 r9 o5 Y2 V2 U
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ E! {) V7 I5 |1 Y5 J3 S. s7 {) \3 Wtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone( w) J% y' h1 M2 K# m+ R3 h) P) {
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent9 O7 F0 c9 M% j4 F( N! O+ P0 \
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% x7 U8 y$ O1 N# dincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ z  i0 ?% N5 _( a. f% bincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response; i0 s7 z7 n% Y
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
* I# b5 Z# P( Z. ?* c7 jstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile( ~8 Y4 a  s" H6 b2 G* }$ g
growth. The response appears to be greater in younger children, which is consistent with previ-9 N2 w$ g; R( P4 X/ {$ F6 e  k" c
ously published studies of age-related 5 reductase activity.1 b8 m7 r' E1 K1 E! c
Children with microphallus regardless of its etiology will. t" F. `0 B" P$ d
require augmentation or consideration for alteration of exter-6 O, f/ e* ]1 y3 X, _- N
nal genitalia. In many instances urethroplasty for hypo-  w: K5 i% v% r& ^9 ~3 v
spadias is easier with previous stimulation of phallic growth./ c9 O* y& O: \! t  G3 [5 c
The use of testosterone administered parenterally or topically1 k* Z% G( |2 h% ?4 d2 \
has produced effective phallic growth. 1- 3 The mechanism of
3 n! P* g$ E8 X( _response has been considered as local or systemic. With this
; q' T- [) i' uin mind we studied 5 children with microphallus for response
( F- O5 v$ j' A/ ^to gonadotropin and to topical testosterone independently.- `& @: s2 X# L+ K; r- J3 f5 u
MATERIALS AND METHODS
0 a% U) b! g$ o( W7 dFive 46 XY male subjects between 3 and 17 years old were9 `4 m* k$ L6 ~6 F* [% t
evaluated for serum testosterone levels and hypothalamic
/ w; X+ K, _* A' H* Mfunction. Of these 5 boys 2 were considered to have Kallmann's, ^* Z6 F: r! \2 D7 c
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 c1 ~* ]+ Z$ M  S
lamic deficiency. After evaluation of response to luteinizing
$ O# I3 d- C4 C' {1 |' nhormone-releasing hormone these patients were treated with
0 I/ e+ F% H% |3 d9 c0 Z& F1 D1,000 units of gonadotropin weekly for 3 weeks. Six weeks
/ N: Q# ^4 p7 h, t1 i# gafter completion of gonadotropin therapy 10 per cent topical* g) D. d7 X# h  d/ U
testosterone was applied to the phallus twice daily for 3 weeks.
5 D) j8 x: ?/ Z$ |' eSerum testosterone, luteinizing hormone and follicle-stimulat-
5 K7 ?3 U& ^- K- T3 p' King hormone were monitored before, during and after comple-
2 U1 ^: m; Y# I* htion of each phase of therapy. Penile stretch length was" G) ~. Z2 }# i9 r
obtained by measuring from the symphysis pubis to the tip of6 l, D1 `  N8 ~* i4 B. I
the glans. Penile circumferential (girth) measurements were) \4 f. L! q0 }0 |/ k
obtained using an orthopedic digital measuring device (see
4 H7 c$ ?4 h. m+ p% o* Nfigure).9 |. I9 P8 y  c5 q5 ^
RESULTS5 K& J. _9 m4 y" W6 J( P
Serum testosterone increased moderately to levels between8 c/ {  E1 a* }9 t
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ k( Y( L: R8 @1 `8 Nterone levels with topical testosterone remained near pre-, O$ S( Y+ ?4 c7 f( q6 a
treatment levels (35 ng./dl.) or were elevated to similar levels
& e0 A+ Y; u2 H, ndeveloped after gonadotropin therapy (96 ng./dl.). Higher7 w2 m  |. E# J. L
serum levels were noted in older patients (12 and 17 years old),9 U8 O% o* D2 v) @; {; L
while lower levels persisted in younger patients (4, 8, and 10
: [% r$ Z. J2 m# X$ o2 qyears old) (see table). Despite absence of profound alterations
+ b5 q% i: I7 nof serum testosterone the topical therapy provided a greater3 F9 ]# Q! Y4 b. `/ g& }
Accepted for publication July 1, 1977. ·5 r, Y, Z: h- E$ r" x
Read at annual meeting of American Urological Association,
& f  U! E8 @2 u8 b3 U! HChicago, Illinois, April 24-28, 1977.9 K7 w+ D9 x) l# w2 Y$ [8 n9 S
* Requests for reprints: Division of Urology, Henry Ford Hospital,
4 T  f2 B; {( s8 c. x2 s& R9 W: I/ W2799 W. Grand Blvd., Detroit, Michigan 48202.0 o! F" V+ l) v) ~0 N% C1 Y' b
improvement in phallic growth compared to gonadotropin., v+ s4 E2 ]: O6 p- b2 ~) b+ `8 N$ z
Average phallic growth with gonadotropin was 14.3 per cent7 {, F" ]' w3 S, d! Y
increase in length and 5.0 per cent increase of girth. Topical; j- ~: K' I; T4 x. U0 u* s
testosterone produced a 60.0 per cent increase of phallic length& O# ]; ]& F. D9 B: T/ C
and 52.9 per cent increase of girth (circumference). The
/ k. X4 d& b" F+ }; ]# presponse to topical testosterone was greatest in children be-
! C# W( T& O& g, L( Gtween 4 and 8 years old, with a gradual decrease to age 17
5 w, V2 F- p9 ]4 Yyears (see table).
  u" Q% X# x7 V, X8 s% H  }DISCUSSION
- F6 T% n+ [, S, P4 M% ?" t8 i  gTopical testosterone has been used effectively by other) _) o/ N( M1 r( T% O
clinicians but its mode of action remains controversial. Im-3 f. ^, O4 B0 b1 X
mergut and associates reported an excellent growth response5 S8 Q4 t$ x& O) b3 m
to topical testosterone with low levels of serum testosterone,7 {. E: Y. t/ r8 X3 z8 h
suggesting a local effect.1 Others have obtained growth re-6 m( Z" L4 }  Q" d- T" D- E
sponse with high. levels of serum testosterone after topical
  c: k& H2 c' uadministration, suggesting a systemic response. 3 The use of
/ a- K  }  ]& g; T) |/ P; t# C2 }gonadotropin to obtain levels of serum testosterone compara-
8 h# X1 I! [* J' b% K. J7 }ble to levels obtained with topical testosterone would seem to! r( K1 y& k: J  B$ z. l
provide a means to compare the relative effectiveness of  M# |0 O- H) }& x' s1 R$ W
topical testosterone to systemic testosterone effect. It cer-8 w- u3 R) i- F
tainly has been established that gonadotropin as well as par-
2 G  R& ^8 O% g7 B8 J' M$ ?0 Centeral testosterone administration will produce genital
+ D3 [. m' E( s" ygrowth. Our report shows that the growth of the phallus was
; C; ]' O5 q) _+ `- w1 esignificantly greater with topical applications than with go-
: f- B$ s; o- ^: a3 ~+ T+ e& T) S* unadotropin, particularly in children less than 10 years old.
5 B$ Y5 ~8 r( M6 CThe levels of serum testosterone remained similar or lower& b5 ~6 n1 _; {( z/ m% @
than with gonadotropin during therapy, suggesting that topi-
5 U- ^# ^/ T& b1 ^cal application produces genital growth by its local effect as
0 f& }$ p; r6 V2 ]( m1 r/ B5 c) `well as its systemic effect.0 X. N# S$ e% U% ^
Review of our patients and their growth response related to" X; l2 @3 e( m) N% y4 y4 t9 I6 P1 T
age shows a greater growth response at an earlier age. This is" |% f# X$ F1 T; M$ v% f+ H
consistent with the findings of Wilson and Walker, who, S: Q/ }" t5 F& D5 A1 J' [, d
reported an increased conversion of testosterone to dihydrotes-
5 n6 A6 Y5 N% V/ Ntosterone in the foreskin of neonates and infants.4 This activ-0 {3 _; ~9 O# u3 F& |
ity gradually decreases with age until puberty when it ap-9 P* B, _1 c9 `
proaches the same level of activity as peripheral skin. It may% u2 p; g! J) P1 r) E5 I7 @+ @" V
well be that absorption of testosterone is less when applied at
1 y) ]8 T' ]: W5 b+ L+ Q7 }an earlier age as suggested by lower serum levels in children* w$ A& b. l9 d+ f/ O6 z
less than 10 years old. This fact may be explained by the( ?8 k8 z* k; T  m" H  P6 y3 j, l- {
greater ability of phallic skin to convert testosterone to dihy-8 }) O' u' y3 Q$ m- p
drotestosterone at this age. Conversely, serum levels in older. e5 g2 M1 e% S$ `! y0 T
patients were higher, possibly because of decreased local! V5 E: o$ Y6 Y2 s& v4 w( a
667
% l+ k1 b+ X1 N# _0 W668 KLUGO AND CERNY9 K! M- H  G* L$ e6 n3 H$ B
Pt. Age
; J: J3 O0 n3 B(yrs.)6 `) Q% {" e! F* `+ d: ?
Serum Testosterone Phallus (cm.) Change Length/ B0 k! ?2 h) k4 \9 @7 s" i
(ng./dl.) Girth x Length (%)
4 {7 r% S( ~" y' F4: ^6 a" z) f5 V) _) M( B% D+ _8 I! B2 d
86 A# ~8 d0 l: \% y
10" g9 m+ ^2 v( r+ }/ r! ?
12* j/ G& s2 S8 L* @% `
17
: h2 V  n# H& }Gonadotropin
( b0 v2 s9 n, j) y71.6 2.0 X 3 16.64 z% |0 W! ]8 @
50.4 4.0 X 5.0 20.0
  k; j$ u8 u5 E4 T( w22.0 4.5 X 4.0 25.05 O- I! n  l+ |2 Q" U: c# c
84.6 4.0 X 4.5 11.16 d: S; P) n# ^: ^7 ^4 h
85.9 4.5 X 5.5 9.0+ S: d- S. J' }  T
Av. 14.3
6 a: ]( L" J( Q' M1 p$ h0 \! y4
3 Y% T+ A1 t# N1 L5 z% X8
* u4 |6 S( @/ w/ p9 P10
( Z+ G# p$ B0 v* n' y120 n7 p) B1 g" F8 f# Y" v, z( @- F
17
, a4 R% f. J6 y, u, w9 a8 CTopical testosterone
' X/ Y1 u+ w$ E3 P& x$ m1 L34.6 4.5 X 6.5 85  m/ L0 \" c: d. D3 b6 |2 _
38.8 6.0 X 8.5 70
* _! y4 m( E  g# @0 }40.0 6.0 X 6.5 62.5
" l1 F" t6 A) r1 j93.6 6.0 X 7.0 55.5
8 ^2 K$ M5 S" }& K, A" a9 i4 `- {; f95.0 6.5 X 7.0 27.2
& r. d3 x/ W* k$ g$ _8 b. U- r1 oAv. 60.0
0 i' V' o9 h4 u& Zavailable testosterone. Again, emphasis should be placed on
3 d2 b  {% \1 Q; \, Rearly therapy when lower levels of testosterone appear to
* F# ]% v$ V, `: G2 r0 Mprovide the best responses. The earlier therapy is instituted
" a2 d4 `; b# t' t: j) sthe more likely there will be an excellent response with low
2 A5 V! T$ X( J* E8 o! q, e4 ?1 \serum levels. Response occurs throughout adolescence as- z( k0 \8 ~. G( o2 F: p: }5 U2 f# L- G
noted in nomograms of phallic growth. 7 The actual response2 B" y+ i0 G  [' \
to a given serum level of testosterone is much greater at birth
: A( O" u3 L" n  F) N, K1 yand gradually decreases as boys reach puberty. This is most
/ M& ^; q9 Q6 f( d! z" `likely related to the conversion of testosterone to dihydrotes-
" S9 Y9 _/ [# v$ C/ B7 R3 L6 m. rtosterone and correlates well with the studies of testosterone
7 \8 H; X  e  v1 Tconversion in foreskin at various ages., S! w3 Q" o; A' o9 `, c
The question arises regarding early treatment as to whether
* w2 M2 m- \0 Eone might sacrifice ultimate potential growth as with acceler-
6 }$ y/ ]! g1 ]' o  sated bone growth. The situation appears quite the reverse
$ b$ E4 j7 A% J2 hwith phallic response. If the early growth period is not used: k% _. Z1 s3 T# Q+ Y* H9 }
when 5a reductase activity is greatest then potential growth
- R2 \. ]- R1 D( ?% Wmay be lost. We have not observed any regression of growth( n! Y- U* W4 u4 d# X
attained with topical or gonadotropin therapy. It may well
9 x. k: Z. v4 [; Z- @9 F4 gbe that some patients will show little or no response to any* i% ~4 [, ^% @# s3 l
form of therapy. This would suggest a defect in the ability to
8 x0 @/ l- _! f. ]! gconvert testosterone to dihydrotestosterone and indicate that& w1 z! R6 w9 v  p: u
phallic and peripheral skin, and subcutaneous tissue should
6 K* _: e1 ~" p% `; Ibe compared for 5a reductase activity.
7 |9 p% S) P5 {2 ~5 F0 f$ ~/ TA, loop enlarges to measure penile girth in millimeters. B,
1 a8 w9 g) h% K+ ~* h$ \  P8 ?, Zexample of penile girth computed easily and accurately.
+ h; F$ B0 d8 v5 ~  sconversion of testosterone to dihydrotestosterone. It is in this
- b$ \1 w+ b4 {$ Z6 Polder group that others have noted high levels of serum
$ ~9 ?# a% W% F2 wtestosterone with topical application. It would also appear
7 }' _0 F8 w1 ^. F4 z0 fthat phallic response during puberty is related directly to the
9 A" G( O+ {6 U! J0 Xserum testosterone level. There also is other evidence of local
0 [' L" N' K$ v4 fresponse to testosterone with hair growth and with spermato-
* A% U  X, K( x+ n5 Dgenesis. 5• 6
: |  A% S# X. p" {' R! BAdministration of larger doses of gonadotropin or systemic1 @8 g$ }, J4 I- b5 W* V
testosterone, as well as topical applications that produce
& r4 q% P. c/ f$ n/ P0 w4 b, o0 i* Shigher levels of serum testosterone (150 to 900 ng./dl.), will
# [) y' @+ s) M6 ialso produce phallic growth but risks accelerated skeletal. `2 O+ A( `# ~! E& ?% V2 n
maturation even after stopping treatment. It would appear! n! e& q% g7 x4 ^1 g
that this may be avoided by topical applications of testosterone
1 n* c1 L8 P* cand monitoring of serum testosterone. Even with this control7 m& ?3 d3 e+ m' V
the duration of our therapy did not exceed 3 weeks at any- L* C$ J* b, B" S: q
time. It is apparent that the prepuberal male subject may
7 T1 I4 E5 p# B+ V6 d) z2 Gsuffer accelerated bone growth with testosterone levels near
5 Z3 X6 F" N1 q- A200 ng./dl. When skeletal maturation is complete the level of
1 s! a6 C! C7 i! m! `; s' \serum testosterone can be maintained in the 700 to 1,300 ng./
9 R# f3 F! F% s/ Xdl. range to stimulate phallic growth and secondary sexual
1 q+ [- b4 u3 N/ Schanges. Therefore, after skeletal maturation parenteral tes-
( F7 Z$ P& {# r, Otosterone may be used to advantage. Before skeletal matura-
+ r1 @4 r  g! w% E. }9 Htion care must be taken to avoid maintaining levels of serum
! w! z6 T4 f% I! Q1 l& f# N0 {9 Ptestosterone more than 100 ng./dl. Low-dose gonadotropin! E) V/ Y, p! K! m, r7 R& i
depends upon intrinsic testicular activity and may require, R# e6 i- a: l" {
prolonged administration for any response.
4 G6 Y. k: K9 Y% L' m8 S3 ]9 E/ ]0 MAlternately, topical testosterone does not depend upon tes-
" T' p: b" a! W0 b& Z" cticular function and may provide a more constant level of1 Y5 B. R% n8 i7 B9 o3 ]* v
REFERENCES: B' K9 c" Q8 U& q# ]0 B' {
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,. x3 z0 S0 |' T. L: {" c# O6 N
R.: The local application of testosterone cream to the prepub-
% J3 s7 V  j% z) ]1 T! B  g! Oertal phallus. J. Urol., 105: 905, 1971.
( e) W" C5 s6 J% ^2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
0 u- {* _) w& c) }8 ntreatment for micropenis during early childhood. J. Pediat.,+ O2 |! |) Z* b: T& m" s
83: 247, 1973.
! a& d, `% t; a5 Y1 N3 T3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 U8 M; q5 N% k* d% }. W- {& j) V
one therapy for penile growth. Urology, 6: 708, 1975.( A6 S- m3 J9 p2 P
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone; i0 I6 o) d$ I$ d; f! f9 Z  h- @
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( ~2 C. A& q" F: [% X* ^& }
skin slices of man. J. Clin. Invest., 48: 371, 1969.
3 h( b8 G, C6 a/ |5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth' C: H' |3 B. `0 p1 p8 s- e/ r- |
by topical application of androgens. J.A.M.A., 191: 521, 1965.
3 U2 l7 l0 B- M) j) S) Y8 U6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: q: T! r4 ]4 L. t! e$ o
androgenic effect of interstitial cell tumor of the testis. J.$ T' F% f) u8 q% B4 j3 A
Urol., 104: 774, 1970.8 T: P+ Q4 \, k) \! ^
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-' e/ r( h6 R8 o( \" r
tion in the male genitalia from birth to maturity. J. Urol., 48:
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