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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
; l. d0 X" P) D1 D+ CGONADOTROPIN8 L5 ?; \6 E2 {# G( F7 H
RICHARD C. KLUGO* AND JOSEPH C. CERNY
  \' {. n8 x; }1 v4 z+ I/ Q$ NFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan3 n0 |  O) {) t4 {6 O; c: I: Y! |
ABSTRACT
* G$ U# a, o/ V2 QFive patients were treated with gonadotropin and topical testosterone for micropenis associated/ O4 r' m9 H1 o" ?5 {, `- ^4 f
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
8 c6 q# ^" X% Q) T+ ^$ e1 l$ N. _# stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
- F: V% ~  N  M" fcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent( @$ t. `9 X# |9 o+ n2 m
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent) H7 }1 F( ~. \0 L) }
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
/ ]; f, ?" \' U; rincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response8 A6 V1 f4 e  O7 a/ j) ~. q+ }& L
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This- [+ U$ q8 t* ?, P% B! f
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile) D* I0 R5 w  l, s+ C5 y2 M) n
growth. The response appears to be greater in younger children, which is consistent with previ-
0 D8 ~1 `9 U' S+ \$ i; eously published studies of age-related 5 reductase activity.& b) e6 p6 p; x+ N7 f% O1 w
Children with microphallus regardless of its etiology will
1 g. f) Y$ ~9 ?4 p! d8 b6 {require augmentation or consideration for alteration of exter-
$ o1 ]9 k1 M; g. {, Hnal genitalia. In many instances urethroplasty for hypo-
! j# y: y" s! {; O+ `spadias is easier with previous stimulation of phallic growth.4 o: r7 X! s! T" V; `3 i- J, f! x
The use of testosterone administered parenterally or topically% y' |/ K) x" N# y
has produced effective phallic growth. 1- 3 The mechanism of
0 T, [& |( k0 ]. K2 K  presponse has been considered as local or systemic. With this, M9 c' \7 p* g, I) Q
in mind we studied 5 children with microphallus for response. B5 K0 Z9 \; t& Q4 Z- ?
to gonadotropin and to topical testosterone independently., B, \: p5 M) F5 ~
MATERIALS AND METHODS
. A: S% o9 q( @Five 46 XY male subjects between 3 and 17 years old were7 u7 o% k/ Z9 I
evaluated for serum testosterone levels and hypothalamic" R7 {3 _/ h( L6 _% V
function. Of these 5 boys 2 were considered to have Kallmann's3 R3 \/ A" q3 N7 {, _  Z" K  I
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 f. `* b& i/ b4 f5 d; n! c! i) Dlamic deficiency. After evaluation of response to luteinizing
7 |* @% u  P4 D. g& H& Zhormone-releasing hormone these patients were treated with
' W6 G2 L4 A4 Q* ?, u) ]& R1,000 units of gonadotropin weekly for 3 weeks. Six weeks
5 ^/ G& w8 m: n* I! Y8 l3 I9 \after completion of gonadotropin therapy 10 per cent topical
0 r+ k! Y' {9 O8 Xtestosterone was applied to the phallus twice daily for 3 weeks.
2 B' ~$ @8 O0 t/ F/ \3 [& fSerum testosterone, luteinizing hormone and follicle-stimulat-
' ?( p; t$ M0 p$ E0 _ing hormone were monitored before, during and after comple-% _) m- x% |0 N. T
tion of each phase of therapy. Penile stretch length was
5 {: K& X  g/ \# v: Gobtained by measuring from the symphysis pubis to the tip of
3 i3 x' j* O2 W8 x& o# O$ U) cthe glans. Penile circumferential (girth) measurements were
+ j' s, v) _0 Robtained using an orthopedic digital measuring device (see( C2 |9 T  Q8 `2 X8 O  @: [, i
figure).
4 W0 k5 y# Y. Z9 l( ^0 pRESULTS3 `4 c7 l, C! _8 H2 L$ E5 i
Serum testosterone increased moderately to levels between; `% s# R# G1 y& W( d; S4 J
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-( f9 a' T* ]6 z' O. X  }2 U
terone levels with topical testosterone remained near pre-8 T6 f5 M* S! f0 K" r
treatment levels (35 ng./dl.) or were elevated to similar levels
0 D& l8 K" d8 I! q; \developed after gonadotropin therapy (96 ng./dl.). Higher' z4 }6 Y! y$ R# z1 Q( ]% @& ^
serum levels were noted in older patients (12 and 17 years old),3 s, ~1 V2 `- \/ ?0 v6 K
while lower levels persisted in younger patients (4, 8, and 10
2 Z: T; x9 ^7 d% r! V$ Syears old) (see table). Despite absence of profound alterations; a7 w+ z% l9 e" [( W$ f% l
of serum testosterone the topical therapy provided a greater6 d! A6 S/ O; j8 T' l! n4 v3 ~3 E
Accepted for publication July 1, 1977. ·
' k; J5 E1 Q# A+ i$ D& t( _Read at annual meeting of American Urological Association,
5 c8 }7 x  m: z9 y' g& g- rChicago, Illinois, April 24-28, 1977.
8 T: {5 ~: b( c. E1 V$ d* Requests for reprints: Division of Urology, Henry Ford Hospital,, e, h$ _- ^9 x2 Z- U1 k
2799 W. Grand Blvd., Detroit, Michigan 48202.
# _, i% p4 i! l  |- Y% i' Gimprovement in phallic growth compared to gonadotropin.: R) B1 t, d8 b* `
Average phallic growth with gonadotropin was 14.3 per cent, F: w( O  d  X( A1 r$ v
increase in length and 5.0 per cent increase of girth. Topical9 \/ n- n  C" j! y: R
testosterone produced a 60.0 per cent increase of phallic length
) ^2 H' A7 p: xand 52.9 per cent increase of girth (circumference). The; ~' d& i1 y6 S+ C; t8 T
response to topical testosterone was greatest in children be-- c, g1 I$ O5 V# Z: }; j( K' W
tween 4 and 8 years old, with a gradual decrease to age 17% t6 R4 b3 [2 F. Y$ Q
years (see table).$ d) h; Z! M6 p8 S
DISCUSSION) n( b4 e! [. L; b" z5 K
Topical testosterone has been used effectively by other
" K% j% _: }- K6 j; L. i3 bclinicians but its mode of action remains controversial. Im-3 Y3 f% }8 \, S. U( |) {
mergut and associates reported an excellent growth response3 l+ o2 N  U4 ^7 J" B3 |
to topical testosterone with low levels of serum testosterone,; ?; W( ?, Z! _; d0 }9 w
suggesting a local effect.1 Others have obtained growth re-
9 L8 _8 ^: d% X& m1 `: b- qsponse with high. levels of serum testosterone after topical
2 g8 I" s/ t# d7 }. h" a, cadministration, suggesting a systemic response. 3 The use of
* o$ U, b( A9 bgonadotropin to obtain levels of serum testosterone compara-3 K6 a& S  D+ m7 o
ble to levels obtained with topical testosterone would seem to+ x( g& t! L2 ]" t  S0 e
provide a means to compare the relative effectiveness of, ^" {$ n6 C2 d
topical testosterone to systemic testosterone effect. It cer-* o8 |* m5 C1 Y& y* Z; W4 ?9 g8 q
tainly has been established that gonadotropin as well as par-0 T5 R! t) j# ~% i/ z; M
enteral testosterone administration will produce genital6 ]6 X/ q1 O- j1 t6 b
growth. Our report shows that the growth of the phallus was
9 _7 {& t+ ?5 }6 q8 {. s5 Hsignificantly greater with topical applications than with go-
1 T! b& Z+ K9 vnadotropin, particularly in children less than 10 years old.6 E; x7 v0 U% q+ P
The levels of serum testosterone remained similar or lower0 ?7 J- m" f) ~" _& I+ U' N5 \+ W
than with gonadotropin during therapy, suggesting that topi-
9 o2 n- I: s9 I+ n) z' y: y0 Ycal application produces genital growth by its local effect as
: b% s' S0 ^$ g9 cwell as its systemic effect.% x7 Z$ s2 j% y% A8 S* D7 ]8 J
Review of our patients and their growth response related to
3 S5 ?: R& L" l2 _& tage shows a greater growth response at an earlier age. This is3 g* M" A  w6 \& u2 {$ @9 U- u
consistent with the findings of Wilson and Walker, who9 q# \- O6 m9 ~) w  t
reported an increased conversion of testosterone to dihydrotes-
/ I  ~2 Z: d6 m: [9 vtosterone in the foreskin of neonates and infants.4 This activ-4 a1 v! i( m2 e7 o4 j
ity gradually decreases with age until puberty when it ap-9 u2 p7 q* J2 r. h
proaches the same level of activity as peripheral skin. It may9 Q# u9 G4 d. m! [7 ~! r
well be that absorption of testosterone is less when applied at9 h. f3 v* z: i  k7 G4 ]
an earlier age as suggested by lower serum levels in children
7 b1 \! w0 f) S1 m% i0 jless than 10 years old. This fact may be explained by the
' h5 v2 u% E/ `: Qgreater ability of phallic skin to convert testosterone to dihy-
2 u) m' q0 D+ |( e( Edrotestosterone at this age. Conversely, serum levels in older
4 u1 c" G) e# Y9 [) z! epatients were higher, possibly because of decreased local
- Q- L+ R% _. L/ N' D/ z. q667# G* t$ D+ C. ~1 W  D, H
668 KLUGO AND CERNY" v# U. ~' J$ i* b* T) x
Pt. Age
( ]+ X- q; t* G9 ]8 y(yrs.)
2 C" g5 X4 S% V, G. Z- _Serum Testosterone Phallus (cm.) Change Length4 F/ [7 l% n# Y2 K: w
(ng./dl.) Girth x Length (%)
4 d- ?! w; p8 c# {; H( u44 Y- Z" X5 Q2 G) n) U) j
8
5 f- S& \  |$ A9 p' d10* z* D5 o0 e" E% ]
12
/ z* T0 M4 c8 o1 }' S6 Z17
" Q1 F4 E( k# y* j  z; a, jGonadotropin2 I' {2 E6 v, @- r2 _4 d) S
71.6 2.0 X 3 16.6: P2 ^/ D# d; U) G7 {( n
50.4 4.0 X 5.0 20.0/ P( Q/ Q9 }" k3 [# R8 k9 `' l0 S4 y
22.0 4.5 X 4.0 25.0
# A. R: [- Y0 x( [: g) C84.6 4.0 X 4.5 11.1- E5 I9 [9 G4 d% r
85.9 4.5 X 5.5 9.09 n0 U& r6 x6 |2 c% F
Av. 14.3
/ G# ?6 d2 g' }( [3 \2 \% i4 k4
2 X/ d' }3 a# `2 F* t. [" t- J1 t5 ~8
) j- r/ R( ^! c) z' Y! ^! m10
8 E/ E% z) g+ ?0 h12. `# B; z& C5 H$ K
17$ H0 ?) T) ?2 }6 ^- z* |
Topical testosterone) p7 O0 a, F2 V
34.6 4.5 X 6.5 85
4 m7 F1 O2 l6 d  w+ O# V3 f38.8 6.0 X 8.5 70
( m8 K+ n4 g) _9 Y6 I# s, i40.0 6.0 X 6.5 62.5  t  ^( c  ^2 q5 L( n. X0 v
93.6 6.0 X 7.0 55.5: P8 p, }" K/ v
95.0 6.5 X 7.0 27.2
# E- u+ X2 V( n- E  sAv. 60.0
9 u: \' j' ?1 j$ E- R( c, k( [$ h9 T' qavailable testosterone. Again, emphasis should be placed on
. H5 b* M% l. M" k2 A+ bearly therapy when lower levels of testosterone appear to  r# N1 v  x7 c4 _/ R, K
provide the best responses. The earlier therapy is instituted
0 y; k( p) q- q) d% ^( ]9 |the more likely there will be an excellent response with low
5 T  [5 p6 X( qserum levels. Response occurs throughout adolescence as
( ?1 P6 {4 T+ ~& t  Q+ mnoted in nomograms of phallic growth. 7 The actual response# P  ]" `8 p; U
to a given serum level of testosterone is much greater at birth
* H9 V0 Z& {5 `1 b! a; q4 cand gradually decreases as boys reach puberty. This is most
" w) Q6 ]9 i1 w7 j2 @+ flikely related to the conversion of testosterone to dihydrotes-
; i! g& |; l/ X5 ^. vtosterone and correlates well with the studies of testosterone. u. |1 }" `% ^+ K% @
conversion in foreskin at various ages.
* v4 {4 V' S0 _  Y& C" FThe question arises regarding early treatment as to whether% `7 _6 Z5 U) M8 \. t
one might sacrifice ultimate potential growth as with acceler-
& r9 P# K, B/ n$ v8 mated bone growth. The situation appears quite the reverse5 y( ^7 B: v# E/ ?) @
with phallic response. If the early growth period is not used
$ \4 ?+ Y( j* ]3 q* ]3 F* p6 \when 5a reductase activity is greatest then potential growth# p( k/ B& C3 R, C1 b
may be lost. We have not observed any regression of growth
& Y& g* Z  j+ h+ L! a. Pattained with topical or gonadotropin therapy. It may well0 O: `* L3 B1 O3 U
be that some patients will show little or no response to any* u* F3 Q3 n( b, a
form of therapy. This would suggest a defect in the ability to' N7 i0 J% t! j4 U1 P
convert testosterone to dihydrotestosterone and indicate that
! R0 I" B- F9 ~: Jphallic and peripheral skin, and subcutaneous tissue should$ W! H( }( m" N- z: F
be compared for 5a reductase activity.
9 b6 d( F6 `  |# [1 h: n9 ]9 gA, loop enlarges to measure penile girth in millimeters. B,; m+ h4 e5 E5 h" T6 H! B
example of penile girth computed easily and accurately.
: w  l$ f& B" J; F1 I6 H! J5 ]conversion of testosterone to dihydrotestosterone. It is in this! k5 L" s! U" R. f6 _; r) a# T1 O" J
older group that others have noted high levels of serum
6 o" a- ^: u6 htestosterone with topical application. It would also appear
0 i+ ]- T3 z+ l9 L. `7 Jthat phallic response during puberty is related directly to the
1 a2 R% }$ ^# K- cserum testosterone level. There also is other evidence of local
: K3 |$ [; J% Nresponse to testosterone with hair growth and with spermato-
8 O1 Y% K, O- T: Dgenesis. 5• 6
$ m; b- l0 \7 b7 FAdministration of larger doses of gonadotropin or systemic
' _6 \1 H/ s* ~testosterone, as well as topical applications that produce
0 D: y4 }" U  l2 @  Ghigher levels of serum testosterone (150 to 900 ng./dl.), will4 x; l. O% q" |3 \
also produce phallic growth but risks accelerated skeletal. J$ U2 J" {/ ^; g
maturation even after stopping treatment. It would appear# V% ~* ]& k( A- R, [& T1 {8 j. n
that this may be avoided by topical applications of testosterone0 T; S3 s8 w/ Y$ ^5 t8 V) Q, j
and monitoring of serum testosterone. Even with this control
7 N- m9 u' ~/ ]+ C& v6 @# U. Hthe duration of our therapy did not exceed 3 weeks at any
5 h: k* q/ n! Q* s( w9 P) qtime. It is apparent that the prepuberal male subject may
$ ^" J! }* f7 M9 f7 _) F+ Z) ]2 Fsuffer accelerated bone growth with testosterone levels near+ y5 Q$ O  `; X
200 ng./dl. When skeletal maturation is complete the level of
0 S! c. Y8 E% l$ b: v* Nserum testosterone can be maintained in the 700 to 1,300 ng./+ f' X+ [6 k' {0 h
dl. range to stimulate phallic growth and secondary sexual) Z7 @, W' r7 x
changes. Therefore, after skeletal maturation parenteral tes-
1 W# b0 l; ?+ ]: U, O4 S; Ptosterone may be used to advantage. Before skeletal matura-$ k7 g& f/ K7 q% I, s& ?6 \
tion care must be taken to avoid maintaining levels of serum
/ D3 p& ?: O1 ~* R" s- f" d( Htestosterone more than 100 ng./dl. Low-dose gonadotropin; R  x: m+ X4 l. T4 N# f
depends upon intrinsic testicular activity and may require: m1 l# y2 D7 ]/ R1 X) M, b
prolonged administration for any response.' j3 i  i; ~* t" a3 D' N
Alternately, topical testosterone does not depend upon tes-
% M. D' K: h( fticular function and may provide a more constant level of. [& g, u! e0 r, P
REFERENCES
% y" s/ I# H6 k2 n2 _( M1 `2 r1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,% Q- |" Y, p4 ], @
R.: The local application of testosterone cream to the prepub-% B3 w' R. ~/ o
ertal phallus. J. Urol., 105: 905, 1971.9 s$ ?* J, y3 T; a0 s' V
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
3 v7 {& Y# R6 ^treatment for micropenis during early childhood. J. Pediat.,; E8 [* C# e( T
83: 247, 1973.
) b, K  A5 a. R: z+ ^% P  }% Z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-7 ~; z+ r7 ^& ^7 A
one therapy for penile growth. Urology, 6: 708, 1975.
: i* H/ ]+ x& Q: }4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
5 \; i% V' i* d6 l) cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 L* R, f! L, U' \" d
skin slices of man. J. Clin. Invest., 48: 371, 1969.3 d1 a! B7 }! P6 ~" a
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
: t# l: ]( n8 t/ E' l( hby topical application of androgens. J.A.M.A., 191: 521, 1965.
& B: A$ @( |) M- U, i; _9 I2 P" {6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
3 x! q' x! r$ g3 fandrogenic effect of interstitial cell tumor of the testis. J.
# M7 k7 T9 l! wUrol., 104: 774, 1970.
. U( Q2 _2 k. O! @# f7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
- O& k$ m  x8 Y- w5 J2 E* Dtion in the male genitalia from birth to maturity. J. Urol., 48:
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