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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
, m5 x. f1 n4 B6 l  t5 PGONADOTROPIN" N" d9 i$ l! i+ z
RICHARD C. KLUGO* AND JOSEPH C. CERNY" n. Q4 o2 J6 I
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan$ r6 V+ }& J" _: ]3 u
ABSTRACT
$ t. `' R# D2 `. IFive patients were treated with gonadotropin and topical testosterone for micropenis associated
8 i3 i) l. F: mwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-; L) k! U, D4 R  i  K$ `0 g7 c5 _( Q
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
2 O: U. d3 n4 v% t- acream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 V% m! U# v& S
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent7 R3 D: P! l* u+ L
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 j2 A' T9 F+ {; d4 K. M9 P' Vincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response) p8 O8 y& w+ j. P
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This+ a$ U% p5 L6 w. R/ b% D
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- c, Z9 D+ {6 [; A3 ngrowth. The response appears to be greater in younger children, which is consistent with previ-2 W" B9 X! Z' _# g; f
ously published studies of age-related 5 reductase activity.
& R4 L: L1 ^2 O* U7 {% ^* U: [Children with microphallus regardless of its etiology will% |! B7 t8 t6 M
require augmentation or consideration for alteration of exter-* `' V) r, v. r# q8 R
nal genitalia. In many instances urethroplasty for hypo-
) t9 W# A+ M, w, Espadias is easier with previous stimulation of phallic growth.
, q0 t0 Z" F, v; B! U4 N. yThe use of testosterone administered parenterally or topically: J  Q% x6 c4 w( O; M& }+ i' c
has produced effective phallic growth. 1- 3 The mechanism of
+ {+ e9 ~/ k* A6 Y; Yresponse has been considered as local or systemic. With this4 |  [% a0 }, `4 g  X
in mind we studied 5 children with microphallus for response
- s/ i/ a- z4 _" J3 kto gonadotropin and to topical testosterone independently.
9 A1 R/ ~/ q+ s' d  S) sMATERIALS AND METHODS
% G" _; u3 Q# d! s3 \2 g' HFive 46 XY male subjects between 3 and 17 years old were
" _  v/ h9 U; h9 ?: Aevaluated for serum testosterone levels and hypothalamic/ q* z$ W2 N9 w" v# h
function. Of these 5 boys 2 were considered to have Kallmann's5 f, ^2 g2 x' [+ m$ ]
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-* z; f1 @/ R! [3 h+ x3 |5 y* G& n
lamic deficiency. After evaluation of response to luteinizing4 D8 R) p# z! `' a& X
hormone-releasing hormone these patients were treated with
* D( G6 R" m/ a  `1,000 units of gonadotropin weekly for 3 weeks. Six weeks/ f, V% L) l; t! s. O. G% E
after completion of gonadotropin therapy 10 per cent topical- k5 V( f% X0 r% a
testosterone was applied to the phallus twice daily for 3 weeks.$ z+ F" h. a7 i! |) \/ O$ r: z
Serum testosterone, luteinizing hormone and follicle-stimulat-
( y2 X# @1 Q% n6 Hing hormone were monitored before, during and after comple-
9 y: o0 ~. u0 j- M5 ^  S* ltion of each phase of therapy. Penile stretch length was
( f2 R3 R/ o6 K$ tobtained by measuring from the symphysis pubis to the tip of
0 R, u, X. u' }6 S: Tthe glans. Penile circumferential (girth) measurements were
% _7 a+ {+ f4 Lobtained using an orthopedic digital measuring device (see
/ {) g/ z2 J- a; ^, [8 l6 I1 B! ufigure).* n6 z( ~' g3 r8 A: i* N; H7 |$ L- I  b
RESULTS
4 u4 ^; c9 Q+ q% ZSerum testosterone increased moderately to levels between& M+ _8 b5 E8 r  Y* [; Q2 ^
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-* l" e9 p4 [% o* i# a$ U& ]( Y
terone levels with topical testosterone remained near pre-
9 J& i7 N9 P( P8 R( c+ otreatment levels (35 ng./dl.) or were elevated to similar levels
9 S& u4 k: _: Hdeveloped after gonadotropin therapy (96 ng./dl.). Higher; v( e. J- g8 E
serum levels were noted in older patients (12 and 17 years old),
" V. d, d$ ~7 G5 m# xwhile lower levels persisted in younger patients (4, 8, and 10" n8 {) {* W7 L  N+ r# q
years old) (see table). Despite absence of profound alterations
! t- B5 y+ h) b* @' bof serum testosterone the topical therapy provided a greater
9 O  c0 E; R- MAccepted for publication July 1, 1977. ·- I7 E& a5 ]  L1 Z' x+ {
Read at annual meeting of American Urological Association,
  K1 Z8 D. `' |3 mChicago, Illinois, April 24-28, 1977.. u6 O) L6 o& q, s2 B+ K9 M
* Requests for reprints: Division of Urology, Henry Ford Hospital,# w& r2 L  l! m1 |; ~1 D
2799 W. Grand Blvd., Detroit, Michigan 48202.
- v$ B3 p, S# [7 O$ Vimprovement in phallic growth compared to gonadotropin.
% @: J) L, Y# Z" n5 H/ R6 jAverage phallic growth with gonadotropin was 14.3 per cent
# c% T. f8 J& |- Bincrease in length and 5.0 per cent increase of girth. Topical! Z8 E. @; l8 K* E. B0 {% s
testosterone produced a 60.0 per cent increase of phallic length
" r2 w) P% K: |$ G4 nand 52.9 per cent increase of girth (circumference). The
, N2 G8 p. p3 I4 P  Cresponse to topical testosterone was greatest in children be-
2 I0 [. Y, }; o1 [, A7 rtween 4 and 8 years old, with a gradual decrease to age 17) b5 E# O* j2 Z5 G' ?3 m; ^
years (see table).. {. S  e! W4 q
DISCUSSION
8 B# V" r: q% {3 Q( \0 YTopical testosterone has been used effectively by other
& J! D) a) r# {9 dclinicians but its mode of action remains controversial. Im-
- c5 i& U# W4 z5 H$ kmergut and associates reported an excellent growth response
+ H- s% E  H# Uto topical testosterone with low levels of serum testosterone,
% s! X8 x% Y$ [, Ysuggesting a local effect.1 Others have obtained growth re-& b5 p5 F. H1 i, t3 l
sponse with high. levels of serum testosterone after topical# q6 ]( b, r6 d  M, ?
administration, suggesting a systemic response. 3 The use of
# A, U" m" v: u8 m$ p: |; n; bgonadotropin to obtain levels of serum testosterone compara-
' ~, G9 P: [! x4 ?+ Wble to levels obtained with topical testosterone would seem to
6 I7 \+ ^6 }, t8 B" j" B: Vprovide a means to compare the relative effectiveness of+ h# J1 G( e( s' r, x" x" F
topical testosterone to systemic testosterone effect. It cer-; Q' D' g; N; `+ Q" Z/ `
tainly has been established that gonadotropin as well as par-5 n7 \2 f4 {5 d& |. M: {7 ?4 J
enteral testosterone administration will produce genital& {" D5 F) h! [
growth. Our report shows that the growth of the phallus was# B) A: @0 C- y0 ?+ d: a  n# g
significantly greater with topical applications than with go-
; N+ A3 n' \9 [  e4 ^3 tnadotropin, particularly in children less than 10 years old.. A6 b+ e6 G$ M9 a* P
The levels of serum testosterone remained similar or lower) S9 Q' |; W' W1 Y
than with gonadotropin during therapy, suggesting that topi-- M' U, b$ k0 ?9 b! N. U3 B, x
cal application produces genital growth by its local effect as9 b; U, q. D7 x: D; s
well as its systemic effect." f; H/ r" E3 D; Z4 W3 ^4 ?
Review of our patients and their growth response related to
3 S. u, R  B7 Y! gage shows a greater growth response at an earlier age. This is
2 m) a$ e- G8 U* v* ~& Y+ Q+ ~+ \; W- Xconsistent with the findings of Wilson and Walker, who! P+ u) p/ d2 K. U2 q% u2 A8 H, V
reported an increased conversion of testosterone to dihydrotes-' R0 w8 N5 M7 H9 @
tosterone in the foreskin of neonates and infants.4 This activ-
* _+ W8 t8 m9 L3 Z8 {- I: City gradually decreases with age until puberty when it ap-  M+ K. b2 m9 L& b* v. _
proaches the same level of activity as peripheral skin. It may
% q+ s0 [9 Q# L/ \3 p4 t1 fwell be that absorption of testosterone is less when applied at: C# J  k% h# l2 D7 _) x6 F: y
an earlier age as suggested by lower serum levels in children
1 [: t% T% k0 k! d" zless than 10 years old. This fact may be explained by the& \4 o: c; f; q* w$ q+ p" u
greater ability of phallic skin to convert testosterone to dihy-
! F6 s8 I) s' l  C* X2 L3 ]; O& \drotestosterone at this age. Conversely, serum levels in older
! S3 o2 d+ X/ V: i7 E# Y, opatients were higher, possibly because of decreased local" `( m, R  l2 t
667* x. s4 v( i' |$ G, a) ~
668 KLUGO AND CERNY
0 b% J  k$ D" c2 u9 ?6 ~' kPt. Age
9 {$ ^- Z% N7 x) }' a(yrs.)
9 q- }* i8 |1 r; k( SSerum Testosterone Phallus (cm.) Change Length1 [9 r3 D* g6 a! D  F( }+ V8 c. K$ C
(ng./dl.) Girth x Length (%)
8 s. E! y/ k' v4$ l0 M( b% L1 ]0 [) g( `3 Q
8
$ K* r' ?( `% f( N, z10
: ?3 B9 z; T2 ?7 W6 Y% @: k' W* H/ [12+ j/ m9 k& _' [
17& \" ]4 g9 i# O
Gonadotropin
* n- [: {9 N7 U7 H8 Y# P8 j71.6 2.0 X 3 16.6/ b4 a! b# B8 I  F. n
50.4 4.0 X 5.0 20.0
1 y( v0 Q! e& W" q8 w0 l4 Y22.0 4.5 X 4.0 25.0
2 w! T! K% K0 C+ w84.6 4.0 X 4.5 11.1
3 ~$ t7 Y! [9 Z; d* K7 b85.9 4.5 X 5.5 9.0! F# Q! D/ Z. K! r- n* [$ u( m
Av. 14.3$ h( l- e8 g% V- \. d' c
4* i. H; f8 k. n; T( s: O
8
8 Z/ b' j6 {$ X+ J: M3 w$ o" O10
/ j7 y8 K! E7 ~/ k- g5 y  V: L12
# b  V& G- x7 w1 Q: d! W! L# i17) u. B3 o! o: o2 [- ]
Topical testosterone& S- h) {/ J+ h# S- A  G  Y
34.6 4.5 X 6.5 85
3 c* {' P7 F$ ]( L8 E1 Z% G$ X7 g38.8 6.0 X 8.5 700 a3 D$ T, t& o+ f, Q3 x, ~
40.0 6.0 X 6.5 62.5
" u4 ^) B* z8 c3 j) N93.6 6.0 X 7.0 55.5
! d$ y" C: [9 L3 v8 |* \1 o95.0 6.5 X 7.0 27.23 @$ P: r1 ?% `/ G
Av. 60.0/ \, {* n1 E2 C, S9 P* {( r
available testosterone. Again, emphasis should be placed on
3 i+ ^% y: `) N' M7 h' R; Oearly therapy when lower levels of testosterone appear to9 V9 b; H+ x9 x+ {$ v$ G& r
provide the best responses. The earlier therapy is instituted& B& f1 V& ^" H  J  S9 S3 T" o. b
the more likely there will be an excellent response with low; d$ r  d7 i: O& t* T8 |
serum levels. Response occurs throughout adolescence as
/ f# E& U+ f  v: j6 Bnoted in nomograms of phallic growth. 7 The actual response3 _( n. k; f) [( P4 O
to a given serum level of testosterone is much greater at birth  b# L# T0 ]. Z
and gradually decreases as boys reach puberty. This is most6 {& M  _9 X+ P$ Z
likely related to the conversion of testosterone to dihydrotes-, y3 a! t/ c  c3 @
tosterone and correlates well with the studies of testosterone
. E: X- G' G% Q+ E* g* C7 [conversion in foreskin at various ages.; ?: L' e6 C7 _2 `. M2 U
The question arises regarding early treatment as to whether
2 R  k% b* k2 fone might sacrifice ultimate potential growth as with acceler-2 v9 Y3 B6 @+ C9 D
ated bone growth. The situation appears quite the reverse
" W/ Q0 W8 u; Uwith phallic response. If the early growth period is not used
' F) t: Y7 v2 @when 5a reductase activity is greatest then potential growth
- M) \" {/ y9 b: [6 x9 @may be lost. We have not observed any regression of growth* l8 G! L/ V8 t, l9 T& d7 ]; J
attained with topical or gonadotropin therapy. It may well/ H7 E, Z# Q  ?! y' `5 G
be that some patients will show little or no response to any
4 P9 p* E1 L3 \% Z- Z3 `1 aform of therapy. This would suggest a defect in the ability to
+ u7 `% i0 {# d/ {9 f: e! u* Y% V9 bconvert testosterone to dihydrotestosterone and indicate that) |+ c$ [! n1 z2 [/ P7 N! f
phallic and peripheral skin, and subcutaneous tissue should( c/ h' o. ~* R: _
be compared for 5a reductase activity.1 t% }6 E- B* k0 d- u, v
A, loop enlarges to measure penile girth in millimeters. B,& Q# D) d, _" Q! j  ^
example of penile girth computed easily and accurately.% U9 O- q8 X4 ^
conversion of testosterone to dihydrotestosterone. It is in this
4 B7 h- R5 V/ u4 H; ?older group that others have noted high levels of serum
/ K3 ?: {) Q5 h, m  Ftestosterone with topical application. It would also appear
+ v* t# \# e$ C( v  Lthat phallic response during puberty is related directly to the
$ R4 j; L2 f. Xserum testosterone level. There also is other evidence of local
. H: T0 l6 m% H% C+ v# i5 hresponse to testosterone with hair growth and with spermato-/ O' v/ z6 K+ Y1 y
genesis. 5• 6
- R- b7 i5 T' JAdministration of larger doses of gonadotropin or systemic
/ c$ M5 u  t! L. }# ~! C9 mtestosterone, as well as topical applications that produce
2 N0 H8 v$ i) ]# X* rhigher levels of serum testosterone (150 to 900 ng./dl.), will
4 g7 t# |) _2 z$ Q3 P" Jalso produce phallic growth but risks accelerated skeletal
' K3 k: s) t# U: n  lmaturation even after stopping treatment. It would appear
! c) G; H7 E. O4 b( H2 Qthat this may be avoided by topical applications of testosterone4 f# n& U+ L" C, P* e
and monitoring of serum testosterone. Even with this control" O% n) X& t/ q0 l% ]0 q
the duration of our therapy did not exceed 3 weeks at any8 ~8 w  K9 g% _9 c5 n2 F9 E
time. It is apparent that the prepuberal male subject may
" p0 A( W7 |( t9 ^( hsuffer accelerated bone growth with testosterone levels near. t5 ~$ m5 i. ?: {: K
200 ng./dl. When skeletal maturation is complete the level of
8 q3 u" ^7 s; wserum testosterone can be maintained in the 700 to 1,300 ng./
- B1 ?# X# K) |7 i6 U0 p/ gdl. range to stimulate phallic growth and secondary sexual- z% ^2 z: D1 x. o. c1 z' w! ~
changes. Therefore, after skeletal maturation parenteral tes-
5 O0 {0 q2 N" G: V+ Ntosterone may be used to advantage. Before skeletal matura-
0 a& ]' x' L" H* htion care must be taken to avoid maintaining levels of serum
  D' b% j4 L% t/ Q5 [, ktestosterone more than 100 ng./dl. Low-dose gonadotropin
# A/ g3 K* f2 z4 e% gdepends upon intrinsic testicular activity and may require
" F4 i; }6 H- x7 Dprolonged administration for any response.. ?+ S4 r9 i0 O6 A5 {. V
Alternately, topical testosterone does not depend upon tes-
, Q4 {! q+ z% O3 K' sticular function and may provide a more constant level of9 R2 Z1 x' g3 P1 l$ Q2 N9 u1 \
REFERENCES  t/ K) T$ t) n% O
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,9 G* B1 y2 e6 [: r; a9 a$ _
R.: The local application of testosterone cream to the prepub-. ~1 j" z) L- Z
ertal phallus. J. Urol., 105: 905, 1971.* u' h, y: x1 E7 r. L: C
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
% u! l6 R0 [' Btreatment for micropenis during early childhood. J. Pediat.,
0 [( X# y% f, ^9 `83: 247, 1973.
; N0 Y% M/ g4 u" k7 Y# ?3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& q6 B$ E% G: ^$ ?4 A) ^
one therapy for penile growth. Urology, 6: 708, 1975.+ m& ?. {  t' D9 @2 U% h- m0 S2 Y0 F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone/ K' u% D$ S' J* ?4 ?6 ]# X1 Z- e" X
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ E. A/ V7 g( D. }0 |9 d! Y% H
skin slices of man. J. Clin. Invest., 48: 371, 1969.
6 O3 E' q4 R% Z! s, ^5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth1 n! D% j2 `3 R4 D4 e# R# ~
by topical application of androgens. J.A.M.A., 191: 521, 1965.
9 e# S! `* U1 v: K+ U6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
# T* D# t9 l+ y5 F& `# H" Bandrogenic effect of interstitial cell tumor of the testis. J.
* K9 J; H( v  v6 L+ b) c" I7 Y" gUrol., 104: 774, 1970./ p- J/ w% m% C
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( R0 o: V9 t& f8 v# L
tion in the male genitalia from birth to maturity. J. Urol., 48:
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