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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
7 q8 h% S% z' _" p, wGONADOTROPIN3 l0 w' ^7 d9 O- F4 J
RICHARD C. KLUGO* AND JOSEPH C. CERNY
$ P2 k" I- g% {4 {9 MFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan+ o' a7 P. P; m0 r1 l" Q8 ~
ABSTRACT
. v% Y( C& L$ N+ d$ A8 R! ]Five patients were treated with gonadotropin and topical testosterone for micropenis associated
8 w# J5 R( ^. }% Q; gwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-5 r% I1 F0 r* h5 d3 Z) P! l
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
' E% y. R5 Z2 B  Y& T3 Mcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent, ?! r6 Z& m- k9 n/ }
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 D( D6 l- N- ]increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
  ]" x; g: Y+ Gincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
( O1 a1 u  I: D2 Xoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 Q0 P* Z( J' Ostudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile7 l! z+ {7 g4 |. |( [
growth. The response appears to be greater in younger children, which is consistent with previ-
4 C4 _4 ?: [- Q2 G$ n# y6 mously published studies of age-related 5 reductase activity.
; f5 j+ y0 c! l* W2 T0 PChildren with microphallus regardless of its etiology will
  a4 z+ D2 T: J! urequire augmentation or consideration for alteration of exter-
) E6 y9 R) q3 P& f, H& Q( s. m! znal genitalia. In many instances urethroplasty for hypo-
2 K/ R+ L7 {* m6 y: Jspadias is easier with previous stimulation of phallic growth.' w2 j9 o3 Y( O9 ]* j4 c9 b
The use of testosterone administered parenterally or topically
; O+ G! W8 x% k1 r( o( ehas produced effective phallic growth. 1- 3 The mechanism of. A2 U# N$ G2 W- B! P
response has been considered as local or systemic. With this
8 Y" v- p) q  F1 L/ |8 s% Sin mind we studied 5 children with microphallus for response8 r) `; J$ D5 P6 s8 {" p; z
to gonadotropin and to topical testosterone independently.
6 K& x- ~+ n" k" ~MATERIALS AND METHODS
% Z3 l4 c! j  Q+ c4 a0 T' e' {Five 46 XY male subjects between 3 and 17 years old were
% l- C9 x" z) l: K7 Kevaluated for serum testosterone levels and hypothalamic+ R  Y7 U" S/ L4 C
function. Of these 5 boys 2 were considered to have Kallmann's7 G5 F% m3 @+ ]5 F3 }6 F
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
/ B* Y( T9 W! J# hlamic deficiency. After evaluation of response to luteinizing9 H4 ^( \! Y4 d) j8 }' o
hormone-releasing hormone these patients were treated with, z5 d7 W$ A  I/ G* b2 c6 ^
1,000 units of gonadotropin weekly for 3 weeks. Six weeks+ v+ x4 g" d+ ~: y" u9 k
after completion of gonadotropin therapy 10 per cent topical* O7 |* l  a0 w
testosterone was applied to the phallus twice daily for 3 weeks.+ z2 H- e/ y* Q7 ?; ~: E" \4 v
Serum testosterone, luteinizing hormone and follicle-stimulat-! x- y4 n$ c0 n+ M
ing hormone were monitored before, during and after comple-/ v4 a. X5 M, r& H3 j9 U
tion of each phase of therapy. Penile stretch length was3 L2 n  l$ F  k& N
obtained by measuring from the symphysis pubis to the tip of
/ t# ?$ s' O* q# s# \$ w, \the glans. Penile circumferential (girth) measurements were
8 P9 u- P3 L# T, Y, K2 @) Vobtained using an orthopedic digital measuring device (see( G4 f9 {+ ]$ A( {! H
figure).
  R5 E% A+ W9 r( QRESULTS+ i* q7 }9 [/ Z" w
Serum testosterone increased moderately to levels between5 N4 O$ m! l: p2 o
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# I3 f9 u4 a# g$ o5 S; D$ pterone levels with topical testosterone remained near pre-9 |& `/ a) ^5 Y' o
treatment levels (35 ng./dl.) or were elevated to similar levels
3 z2 ?$ g+ m1 U' I4 p& o$ D0 Q' A! kdeveloped after gonadotropin therapy (96 ng./dl.). Higher
# _& m4 G' b* d5 @( Z% z) T0 Iserum levels were noted in older patients (12 and 17 years old),3 A% U' U  {8 B5 q4 B8 r- G
while lower levels persisted in younger patients (4, 8, and 10- v5 {& e- }# H% k8 C, H2 ]0 \
years old) (see table). Despite absence of profound alterations
* O- n  f$ H! Qof serum testosterone the topical therapy provided a greater
9 _* m! e( v. ]7 Y: KAccepted for publication July 1, 1977. ·
* N' D# }* x/ M# \, s9 x. }Read at annual meeting of American Urological Association,
. y: t" c# n1 w) s' U6 a' D& jChicago, Illinois, April 24-28, 1977.1 V! Y+ ]3 M! k0 \' a
* Requests for reprints: Division of Urology, Henry Ford Hospital,2 ?5 \4 J+ _3 R- [
2799 W. Grand Blvd., Detroit, Michigan 48202.
* E0 C5 P. s9 [. Eimprovement in phallic growth compared to gonadotropin.
5 p$ l% V! {0 N6 I. m' ^$ CAverage phallic growth with gonadotropin was 14.3 per cent4 k. m; R' ^/ u& `, ?
increase in length and 5.0 per cent increase of girth. Topical4 o- P$ q. O! Q/ W2 C( R* `7 x% b
testosterone produced a 60.0 per cent increase of phallic length
- C5 u* y! Z( f" U/ ?* fand 52.9 per cent increase of girth (circumference). The
  d. t) U" ]8 y& ~2 Q$ _! g7 Mresponse to topical testosterone was greatest in children be-
, J! `8 A: P: M$ {tween 4 and 8 years old, with a gradual decrease to age 17' m& x& o9 d( j
years (see table).0 J% a$ J2 @$ S0 H$ h. E+ c
DISCUSSION
# }, U/ J) s) j8 C, f) f! w- p$ iTopical testosterone has been used effectively by other
, ^0 \" k! }1 G3 c) q0 Fclinicians but its mode of action remains controversial. Im-" y2 u4 e% z1 m; B5 n. c& V
mergut and associates reported an excellent growth response- Z- S; N9 Q1 S5 E2 x% [, v0 L
to topical testosterone with low levels of serum testosterone,
: w7 l; B! y2 B" O5 F+ wsuggesting a local effect.1 Others have obtained growth re-( o& H" m8 B' Z7 d6 ]' [2 l
sponse with high. levels of serum testosterone after topical5 m; N- u8 J5 H3 N9 C3 }
administration, suggesting a systemic response. 3 The use of
+ u1 M4 u: t  d' N" ogonadotropin to obtain levels of serum testosterone compara-
: c* O) @; K8 b. Xble to levels obtained with topical testosterone would seem to
% f% N, _. N$ Iprovide a means to compare the relative effectiveness of
, ~5 A2 |) Y7 f$ p- U4 b( A% btopical testosterone to systemic testosterone effect. It cer-+ r3 q& w+ t2 z* {2 J% V
tainly has been established that gonadotropin as well as par-
2 o0 p9 ?$ M7 G) z9 jenteral testosterone administration will produce genital2 [5 w. m9 n, [& d5 e. R' W$ v
growth. Our report shows that the growth of the phallus was
" Q' G! M, m! I! lsignificantly greater with topical applications than with go-* q1 i' I) ~; ?) j, {  D" y. S! o
nadotropin, particularly in children less than 10 years old.
$ R& I4 x2 x; y" Z$ kThe levels of serum testosterone remained similar or lower
" d# u+ d- ~) M' G* E5 u1 o, mthan with gonadotropin during therapy, suggesting that topi-* ^/ \8 G9 x9 @; h0 h, k
cal application produces genital growth by its local effect as
3 y1 G( K7 E' q& ~1 W+ rwell as its systemic effect.
# s8 Y( @2 N2 L( @( L$ DReview of our patients and their growth response related to% x$ n. T8 N# I8 `7 p
age shows a greater growth response at an earlier age. This is. K6 D0 W, h% P" m+ [3 s6 k
consistent with the findings of Wilson and Walker, who
$ k: T# E+ g" h& [) s4 Jreported an increased conversion of testosterone to dihydrotes-
' x) t: b. `6 d  {8 Atosterone in the foreskin of neonates and infants.4 This activ-
$ r  B0 N+ o' \; y* ]+ r1 Uity gradually decreases with age until puberty when it ap-6 N8 `; V. W" p/ I6 B; ~
proaches the same level of activity as peripheral skin. It may
" u6 X7 D! b. f6 X# t2 y4 P% M7 ?well be that absorption of testosterone is less when applied at
; ?8 V& t& O( W* |& Lan earlier age as suggested by lower serum levels in children
9 v# m/ i/ \3 ?+ Nless than 10 years old. This fact may be explained by the. Z; }/ W5 c1 Z) D- x. E' _6 v* ~
greater ability of phallic skin to convert testosterone to dihy-
( B2 R; \4 g8 q8 M+ e+ b$ L+ Ndrotestosterone at this age. Conversely, serum levels in older8 r) i# l. E( Q( q# [$ T. ]( O
patients were higher, possibly because of decreased local1 L. j; Q" H# i3 }# ?3 S$ r1 n
667( [5 }; B$ q0 l$ M' y
668 KLUGO AND CERNY
$ x( B$ b3 z# RPt. Age" a, }7 I7 E0 k& J
(yrs.)9 q8 W) T: e) [7 |
Serum Testosterone Phallus (cm.) Change Length
% I/ x/ l; _8 {3 Y1 v$ i(ng./dl.) Girth x Length (%)
' F% I2 G$ T7 b# ^& }42 n9 c$ C; ?1 a: s
8
( ]0 A- S& `0 e( f: i1 G& p10' i( w$ g- J/ i4 g
12
9 I7 a; m$ S& o+ g& Y. t- S* S17
0 g' ~: ]! ]  B+ N( J% J- HGonadotropin
( P! l8 {+ `0 Q0 o) N' V71.6 2.0 X 3 16.67 F0 d+ W! H! m- A" C
50.4 4.0 X 5.0 20.03 w# j6 `( Z9 ?. C: n! N
22.0 4.5 X 4.0 25.0, E0 `- J4 G; j+ r' D
84.6 4.0 X 4.5 11.1% C  ^0 e4 F9 _- D3 S* g1 p
85.9 4.5 X 5.5 9.0
3 ?! B, Y% S7 U' L, IAv. 14.3
* h/ \& O; C% z; l6 s4# Z" F' i0 q) w& ~
8; l( r" D2 t  m! H5 T0 y
10
- r  O/ Q) y) p1 g% {' j8 T12
  |3 q3 o# v% ?7 e) o6 {% p17
& m- A7 b0 P/ l7 N" A* y) @4 WTopical testosterone3 P1 D7 Y( ^: ?9 }: l  `6 P( j
34.6 4.5 X 6.5 856 ?0 E% _- f* t7 Y  [6 p
38.8 6.0 X 8.5 70" U% s; E4 Z' d
40.0 6.0 X 6.5 62.5
0 C3 B% |1 b0 n7 D" O; Z93.6 6.0 X 7.0 55.59 O9 T+ t. x" ^9 q* U
95.0 6.5 X 7.0 27.2
8 j7 ?0 T. M) M! w& U1 FAv. 60.0
2 [1 v9 g9 c, i/ G. aavailable testosterone. Again, emphasis should be placed on
0 W  e2 a5 g6 dearly therapy when lower levels of testosterone appear to
1 h9 Q. c- Y$ }4 zprovide the best responses. The earlier therapy is instituted/ X& n) J! ^* ^
the more likely there will be an excellent response with low
, l& Z$ e0 i1 ~; }3 Qserum levels. Response occurs throughout adolescence as, {! l- G% s0 [4 t+ l
noted in nomograms of phallic growth. 7 The actual response& Z& A8 v# ~6 |7 P8 r* J
to a given serum level of testosterone is much greater at birth
; L* G; r/ s2 N+ Q* P2 k# W( Oand gradually decreases as boys reach puberty. This is most
! y8 v& \/ J  O  y  }& n; Llikely related to the conversion of testosterone to dihydrotes-
/ e3 F. d) M0 {& Dtosterone and correlates well with the studies of testosterone
5 G8 z1 j0 ~5 s' hconversion in foreskin at various ages.1 y3 F* B% m8 ?# @1 S
The question arises regarding early treatment as to whether0 n7 h8 X) M$ H: P0 M
one might sacrifice ultimate potential growth as with acceler-2 ?, Q! p8 l$ C
ated bone growth. The situation appears quite the reverse. B5 d$ x% U* i$ O/ f
with phallic response. If the early growth period is not used0 x. M  ?# E  M
when 5a reductase activity is greatest then potential growth0 I: |' l8 `6 E; D/ f
may be lost. We have not observed any regression of growth
8 K' y0 x. |$ S0 Y: Dattained with topical or gonadotropin therapy. It may well
7 g' t% ]% `3 m9 bbe that some patients will show little or no response to any
" i8 F% V/ C/ K" Y) U% X9 _+ kform of therapy. This would suggest a defect in the ability to
) [4 y( m# n3 K" mconvert testosterone to dihydrotestosterone and indicate that
" N1 Z$ u$ n9 m  s& b2 Z& F6 Bphallic and peripheral skin, and subcutaneous tissue should
$ b8 Z; l) K5 Dbe compared for 5a reductase activity.
4 D/ Y  Q! K( S4 {A, loop enlarges to measure penile girth in millimeters. B,
0 G0 {6 ?. i0 m5 h1 D3 Xexample of penile girth computed easily and accurately." W' G" f2 }( w8 B
conversion of testosterone to dihydrotestosterone. It is in this
' S$ _* d* N0 V, G' o: Molder group that others have noted high levels of serum6 i$ x! U/ N* r9 U4 I# |- T
testosterone with topical application. It would also appear
- |. N7 X* n: f* {! p9 i) \that phallic response during puberty is related directly to the
3 E1 u' E# S0 R  Pserum testosterone level. There also is other evidence of local- A- w" o) A# K3 x8 ^
response to testosterone with hair growth and with spermato-
/ {' a# }; Y% r/ ^genesis. 5• 69 v! z" Q* I" T% t7 v# o  e) `
Administration of larger doses of gonadotropin or systemic1 D; y7 c/ a/ e& D* Q5 t* F' y$ {
testosterone, as well as topical applications that produce
4 y  R  M# L& Q" \- @1 `0 Hhigher levels of serum testosterone (150 to 900 ng./dl.), will
- {. P% g5 y, Z$ o6 F5 @also produce phallic growth but risks accelerated skeletal3 ]. _7 t7 T% g; }
maturation even after stopping treatment. It would appear
2 X& ^8 w- ?3 vthat this may be avoided by topical applications of testosterone0 D& u* e7 t+ i% u
and monitoring of serum testosterone. Even with this control+ q. Z' R/ x- W6 \
the duration of our therapy did not exceed 3 weeks at any
; u, j: P( L$ A* c- Wtime. It is apparent that the prepuberal male subject may
; X; V: ]. R/ z0 a. x: `. Xsuffer accelerated bone growth with testosterone levels near
5 z2 _# N" V  V200 ng./dl. When skeletal maturation is complete the level of, H/ a2 `2 e5 Q2 K8 V$ \
serum testosterone can be maintained in the 700 to 1,300 ng./6 w1 i8 i: @! C
dl. range to stimulate phallic growth and secondary sexual
4 ^1 j3 W$ C& q* q+ {9 \% \7 echanges. Therefore, after skeletal maturation parenteral tes-9 ]. T# C2 W. a7 A4 X, L
tosterone may be used to advantage. Before skeletal matura-
: l- _% ?4 P! X. N/ J4 ?3 htion care must be taken to avoid maintaining levels of serum
& T8 O) Z2 }+ D4 etestosterone more than 100 ng./dl. Low-dose gonadotropin
! J/ Q0 V/ c" ]# `' edepends upon intrinsic testicular activity and may require
  W9 k% A; }4 {8 q# Vprolonged administration for any response.
" s/ r) e1 w" |0 u2 f# [Alternately, topical testosterone does not depend upon tes-/ D2 a$ b" A. t: X+ u5 N0 Q8 m! |
ticular function and may provide a more constant level of' n  b/ V0 L9 [: H" e( c2 a! A
REFERENCES
1 f" y( o/ H" F$ e, X: y9 @1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,7 D4 ?- A2 P: M8 E
R.: The local application of testosterone cream to the prepub-, f  J9 @3 w$ s+ D
ertal phallus. J. Urol., 105: 905, 1971.* ?1 y$ l1 {8 t+ v* z: V: a8 ]
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# Z! }# i+ `+ Q( K
treatment for micropenis during early childhood. J. Pediat.,4 b. f2 _1 Y7 T7 P
83: 247, 1973.
6 F) X5 `0 ?( S* g  _7 @/ l1 ~3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
; V2 C! _6 ]! p( j# _, |* w' c7 l- Ione therapy for penile growth. Urology, 6: 708, 1975.
9 O6 M5 K* S. `0 T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone8 V! q4 s0 v# G4 K- K
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 |- }. s/ A$ O3 W' `  Q
skin slices of man. J. Clin. Invest., 48: 371, 1969.5 a/ z/ ?- `2 h' ]$ C; W
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
" Q, l; @/ O" q% qby topical application of androgens. J.A.M.A., 191: 521, 1965.( r& G$ L' o: J: O( X
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
. M' M# J3 t5 g3 Z5 h; J( A3 uandrogenic effect of interstitial cell tumor of the testis. J." y$ Q4 i4 \- d, _0 q7 t( X. d
Urol., 104: 774, 1970./ {/ G+ P) }! |& j) ^8 O; S
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-" @+ h5 Y: U  Z2 g+ H8 ]7 @* ?0 t
tion in the male genitalia from birth to maturity. J. Urol., 48:
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