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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND( _6 o' y: w  d  }, [6 z& E
GONADOTROPIN, m3 }8 `1 x4 |9 M0 d
RICHARD C. KLUGO* AND JOSEPH C. CERNY
2 \% k3 `+ D1 U2 i& k( GFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
4 t" q0 H9 Z& \- R# [ABSTRACT
7 H6 Q, |- E7 C  y" q- `Five patients were treated with gonadotropin and topical testosterone for micropenis associated9 ?9 j' ^/ W" j& Y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-. k9 Z1 |* G! a, I
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone  O3 o9 z4 Q8 N  G% g" D# e
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
2 ?  ~- x% q2 pfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent; ~4 V3 @$ R3 s
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average! T7 z8 |( Q6 c+ g9 f& W6 i
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response2 c6 ~8 [: Z8 U3 S# P2 A. o4 L
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 C5 V* _# W  G/ z) |
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
( X! r1 e7 Y9 y% ]growth. The response appears to be greater in younger children, which is consistent with previ-
( J& N( `6 s+ O! }5 s- ]" K9 o; U2 Eously published studies of age-related 5 reductase activity.$ A; X: U2 {$ Y+ D/ a# J( p" K
Children with microphallus regardless of its etiology will
# W1 O: f* n! \  e4 Srequire augmentation or consideration for alteration of exter-  `, p- d) X1 G5 o7 I# T1 E4 ~
nal genitalia. In many instances urethroplasty for hypo-
2 G7 }* f4 \6 v( p8 W/ ^. x, {spadias is easier with previous stimulation of phallic growth.3 V/ A5 h  {4 Y9 L
The use of testosterone administered parenterally or topically
' L% U) E/ r8 ]6 b; Ghas produced effective phallic growth. 1- 3 The mechanism of
. E& @3 U6 K: F5 S" o! R# Lresponse has been considered as local or systemic. With this. a* m6 _. j; W( m2 K
in mind we studied 5 children with microphallus for response8 }' P# @' O  {2 Q8 Z/ J/ m$ B
to gonadotropin and to topical testosterone independently.  ~# K0 R9 D3 h' B9 u
MATERIALS AND METHODS* R: s5 a2 ^& ~8 A) {: V3 W
Five 46 XY male subjects between 3 and 17 years old were  _# C; v5 i/ Y% p6 M7 s6 N
evaluated for serum testosterone levels and hypothalamic9 F) f) T. b* k" D, u
function. Of these 5 boys 2 were considered to have Kallmann's4 G" E. D! P3 b
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
7 S( m: J1 y" v8 e2 |lamic deficiency. After evaluation of response to luteinizing
' j6 i: a* k# O) B$ @: Ihormone-releasing hormone these patients were treated with8 x) ?$ M- _" y9 [! \; }& |5 \" l1 [
1,000 units of gonadotropin weekly for 3 weeks. Six weeks# p- p$ L& K3 J
after completion of gonadotropin therapy 10 per cent topical) ?% D' F6 f- l1 j" l: @! }; r& K9 o
testosterone was applied to the phallus twice daily for 3 weeks.# a7 _/ O3 g9 c  b
Serum testosterone, luteinizing hormone and follicle-stimulat-
3 Y' f" A& K: Hing hormone were monitored before, during and after comple-$ E3 a  B* F0 }5 ]. u
tion of each phase of therapy. Penile stretch length was
0 W( A+ L# d) T' T- i# _obtained by measuring from the symphysis pubis to the tip of
6 F1 t0 M; p4 pthe glans. Penile circumferential (girth) measurements were- W" Q! R# Y) [& s/ @* b  P5 o
obtained using an orthopedic digital measuring device (see
$ t. J$ X# R6 Ufigure).
5 J7 L+ x9 O, M) CRESULTS" w* ]5 _4 x3 f) Z  q* R% c; |
Serum testosterone increased moderately to levels between" R$ C6 e8 F" y4 h' F
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# M9 P) \$ k3 ^1 z  E) c" vterone levels with topical testosterone remained near pre-
2 I3 O: Z* y4 U& o; {treatment levels (35 ng./dl.) or were elevated to similar levels
4 [! s# O. U/ n! y' ~/ kdeveloped after gonadotropin therapy (96 ng./dl.). Higher
7 O7 d) H! c$ X# t+ tserum levels were noted in older patients (12 and 17 years old),
: K5 [4 i3 Y8 d0 [0 m/ _while lower levels persisted in younger patients (4, 8, and 10
: D- u( g2 X! {, X* ayears old) (see table). Despite absence of profound alterations/ ]) a7 H" p! h+ {
of serum testosterone the topical therapy provided a greater& t: `( j. Q- M$ [5 `) u, x+ _4 G
Accepted for publication July 1, 1977. ·
# P' I7 |  [) A% o7 _- KRead at annual meeting of American Urological Association,
% B  w9 u4 R% @6 V) e) c8 ]Chicago, Illinois, April 24-28, 1977.+ H  n: x8 |0 k7 l& k: H+ `, S
* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 |* i2 m$ h+ I2799 W. Grand Blvd., Detroit, Michigan 48202.. X' I% O& o" V9 o: j. g
improvement in phallic growth compared to gonadotropin.
2 e# `  [: g+ v# r: _6 x# K2 B+ AAverage phallic growth with gonadotropin was 14.3 per cent7 ~1 v: p0 L0 W, I7 b
increase in length and 5.0 per cent increase of girth. Topical
$ A  F% H6 W: P/ Jtestosterone produced a 60.0 per cent increase of phallic length
4 r  o/ P- A7 J5 ?  |( ?and 52.9 per cent increase of girth (circumference). The
, X* S4 X* h6 p5 N6 Aresponse to topical testosterone was greatest in children be-  j. W" P* S8 q, J& T. B
tween 4 and 8 years old, with a gradual decrease to age 17
( s7 X+ n' U3 }0 t+ v  hyears (see table).# u5 O* \7 o1 n
DISCUSSION7 l& W" D: j% f. {' t
Topical testosterone has been used effectively by other1 \0 s/ W$ z) N, L
clinicians but its mode of action remains controversial. Im-
, {6 S% j  }  @; w" n( bmergut and associates reported an excellent growth response2 K" l. N; J+ f# A  q1 k6 B
to topical testosterone with low levels of serum testosterone,
. b! n* i# F# n3 ?& ]8 r4 osuggesting a local effect.1 Others have obtained growth re-
( q3 B/ M. W/ J2 \1 {  Usponse with high. levels of serum testosterone after topical
) c, H; T) _  G! B" C7 I8 C' Qadministration, suggesting a systemic response. 3 The use of
6 E5 \# c3 r6 U- B4 V! ygonadotropin to obtain levels of serum testosterone compara-5 [* ^4 E6 A( s, @
ble to levels obtained with topical testosterone would seem to
. ]  P- o; y' w6 K, k# Vprovide a means to compare the relative effectiveness of
. \$ ~* n; z$ j) r! p+ `# J( Stopical testosterone to systemic testosterone effect. It cer-
2 U* G& {+ K, ^tainly has been established that gonadotropin as well as par-
: m' v* r/ R2 P6 Centeral testosterone administration will produce genital
' r+ O) r0 @. ?growth. Our report shows that the growth of the phallus was
* V4 T' x0 h- Rsignificantly greater with topical applications than with go-
$ F, D7 @% i; H+ l" a: ]  Wnadotropin, particularly in children less than 10 years old.
$ v' V' @1 F* K* L0 CThe levels of serum testosterone remained similar or lower
: {" g- d! L% d- i( f7 othan with gonadotropin during therapy, suggesting that topi-
1 r2 z4 }3 D( }5 k0 hcal application produces genital growth by its local effect as
* p3 Q9 G) J) |. S/ @, dwell as its systemic effect.$ P. n# B' K/ X* S3 z% j5 P
Review of our patients and their growth response related to: t6 r+ g2 {# [1 M0 \+ b3 l
age shows a greater growth response at an earlier age. This is
% J) y1 |# d% _! mconsistent with the findings of Wilson and Walker, who: B+ d# Y( Q8 r: n1 G: T
reported an increased conversion of testosterone to dihydrotes-1 t3 V: [/ Z& B& r( q. g; X+ ^
tosterone in the foreskin of neonates and infants.4 This activ-
$ @* p3 F# e* D7 j# G1 k8 kity gradually decreases with age until puberty when it ap-
; j! o8 [, K+ F- G: Tproaches the same level of activity as peripheral skin. It may
6 _0 @, s4 o$ o2 P6 z0 ewell be that absorption of testosterone is less when applied at
' o  ]2 x0 P7 e0 ban earlier age as suggested by lower serum levels in children2 B. X1 J. x# c* x2 n' y+ u! T1 N
less than 10 years old. This fact may be explained by the
7 M' d% P& N' H. L5 Pgreater ability of phallic skin to convert testosterone to dihy-
- L0 \, T+ Q# _) Mdrotestosterone at this age. Conversely, serum levels in older
& e$ |( q9 q4 N" K, tpatients were higher, possibly because of decreased local3 q0 J! v! C$ M
667
: }! V9 U% ], I5 J. N' I  J668 KLUGO AND CERNY
  c; X: o% K  U3 T$ {* b4 SPt. Age8 L8 [) t2 V/ K
(yrs.)
: y* s/ I3 ~, ~Serum Testosterone Phallus (cm.) Change Length
: Z; [% c9 n. g(ng./dl.) Girth x Length (%)
  v7 I7 F$ ^* Z. r/ l( I40 G% ~- q9 Q+ \% A0 ]+ I+ f0 E
85 l( O# q3 x$ U$ \: L6 S, y7 U
10
; a) m9 s3 A2 z- G5 \2 b& l12
# p$ g) A+ E) z" q2 [8 z4 K# H5 V17
, r! o8 S/ G2 a% K4 e/ [Gonadotropin- J  f$ y% m0 r& F
71.6 2.0 X 3 16.6
$ J; Q8 @% P+ ?# g( q50.4 4.0 X 5.0 20.0
& J0 E+ C) u! y" t$ Z22.0 4.5 X 4.0 25.0
. ]" z; X0 J- L& T- @84.6 4.0 X 4.5 11.1
3 E+ F2 F- x9 r8 Q3 G85.9 4.5 X 5.5 9.00 E& v) v, x* U5 _
Av. 14.3
$ V: r* a0 i& A, {# a# [: }# ^% v48 z/ K. _+ ], p3 [$ J* P3 ]
8
% |5 I+ Q9 `" `10
6 t' ]' J! Z: X( G: P12
$ Z& F" A" K' A17
/ L$ f) j6 Y  T& t% Z4 x5 PTopical testosterone3 ]  o. j3 W% R
34.6 4.5 X 6.5 85
$ V6 s0 d2 V, g& }4 K38.8 6.0 X 8.5 701 g( U1 y4 h2 e# S: X" e+ L0 X
40.0 6.0 X 6.5 62.5
4 k( G4 k! [  Y) x# Y93.6 6.0 X 7.0 55.5
' D: g4 C( W6 G+ ^: v& F" K95.0 6.5 X 7.0 27.2
% A) P. |) B) O. }Av. 60.0; l( e, i& x5 \2 n. Q% ~
available testosterone. Again, emphasis should be placed on2 B/ ]7 V# g4 _
early therapy when lower levels of testosterone appear to
7 A& n( j. b' i% rprovide the best responses. The earlier therapy is instituted
( Y4 ^: C1 B+ G% athe more likely there will be an excellent response with low+ S* e& t, i, w# X
serum levels. Response occurs throughout adolescence as& n/ C) j* ]- h  `4 ^
noted in nomograms of phallic growth. 7 The actual response* ~# |3 R) H- X3 F5 |, v
to a given serum level of testosterone is much greater at birth
+ N. ?2 N" _( D$ I, q4 pand gradually decreases as boys reach puberty. This is most8 t3 ~+ p/ ~) o  q. @1 k) \, x! ?8 E3 T
likely related to the conversion of testosterone to dihydrotes-
  s0 c2 I6 R2 Q( Ztosterone and correlates well with the studies of testosterone5 W, v: }3 j; F4 `( a8 j
conversion in foreskin at various ages.: i/ v" p0 \1 j! Y
The question arises regarding early treatment as to whether
9 ?3 m; H2 c5 d! N4 Cone might sacrifice ultimate potential growth as with acceler-7 d. W" G  l( l8 m& t
ated bone growth. The situation appears quite the reverse
% I$ m  \. Z! f; s$ {with phallic response. If the early growth period is not used& p0 P! R2 `; @& v) n
when 5a reductase activity is greatest then potential growth7 G; H6 e# K: F- s
may be lost. We have not observed any regression of growth
) f$ C/ M- k' k) [2 Cattained with topical or gonadotropin therapy. It may well: S  H" A# D+ k/ z
be that some patients will show little or no response to any5 U% V1 e% v% r2 ^6 v5 x( v+ a
form of therapy. This would suggest a defect in the ability to3 P2 Y1 X3 X: w% U3 m: p
convert testosterone to dihydrotestosterone and indicate that
9 Z+ ?8 C, Q. E7 t' A. P8 C3 wphallic and peripheral skin, and subcutaneous tissue should
7 v6 a! i* }# G. u  K  I5 {3 Qbe compared for 5a reductase activity.* p- x! L  g8 w9 B$ p
A, loop enlarges to measure penile girth in millimeters. B,7 d$ H$ k3 I0 M& S4 I) X0 ^% E( Q
example of penile girth computed easily and accurately.7 i6 {1 k+ M' D- J4 u. [8 T
conversion of testosterone to dihydrotestosterone. It is in this  h0 F5 o- H/ t! {# C( N
older group that others have noted high levels of serum3 t/ U& C, G; i( F
testosterone with topical application. It would also appear" ^( c5 `/ h' j
that phallic response during puberty is related directly to the
, W" c" ]' `: y9 X& Sserum testosterone level. There also is other evidence of local. k" ~" ~: \# e4 Q; c( r3 V9 ]. z
response to testosterone with hair growth and with spermato-
2 y+ E+ B$ A& |, ?# k! V2 b" @genesis. 5• 61 E* u. H) d! d! W7 p
Administration of larger doses of gonadotropin or systemic
& {0 N/ @* C! m# U8 ]/ W  ytestosterone, as well as topical applications that produce" c% l% b; H+ ?6 p) m
higher levels of serum testosterone (150 to 900 ng./dl.), will
9 G1 p) ]/ H% I3 S& j4 Galso produce phallic growth but risks accelerated skeletal: M9 d/ T" p. {7 f2 ^- m
maturation even after stopping treatment. It would appear7 q( F7 u! I! J; ?9 M5 ~: Y; V
that this may be avoided by topical applications of testosterone& c; I9 B0 \% e' w" _7 V# z
and monitoring of serum testosterone. Even with this control2 `! m, r9 f( [* O4 P) x% \) B+ w
the duration of our therapy did not exceed 3 weeks at any2 B* [' d- d! o1 n
time. It is apparent that the prepuberal male subject may( a# @) x5 i7 k, B! q( W' k
suffer accelerated bone growth with testosterone levels near
1 ?2 O* H2 z9 @: h; Q, Y200 ng./dl. When skeletal maturation is complete the level of1 ?2 T, @) V5 ~! J- ?4 N
serum testosterone can be maintained in the 700 to 1,300 ng./2 ~5 l  S7 k% B' @. s
dl. range to stimulate phallic growth and secondary sexual! g7 m+ M5 ^7 M. S7 i, G
changes. Therefore, after skeletal maturation parenteral tes-( v: l, v4 D+ K: `) a
tosterone may be used to advantage. Before skeletal matura-
" v# Q4 w' F2 b0 Z2 @tion care must be taken to avoid maintaining levels of serum
9 K4 H) t$ y% Dtestosterone more than 100 ng./dl. Low-dose gonadotropin
- T* M  _9 J. }6 m% e& d# H" U- q5 jdepends upon intrinsic testicular activity and may require4 b# A4 H3 m9 v! j: a
prolonged administration for any response.
" d8 L/ n" e3 |9 QAlternately, topical testosterone does not depend upon tes-
; z3 ?. ~% h6 B1 [& i0 S" B8 W1 sticular function and may provide a more constant level of6 D' u) O1 i6 Q5 {4 O9 X
REFERENCES1 t) N0 R" G& V7 \6 S3 S+ }
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- z. Z  C* d% G) t6 X$ s8 Q
R.: The local application of testosterone cream to the prepub-
1 T/ R, d/ j. K7 Hertal phallus. J. Urol., 105: 905, 1971.
8 V  B: t- A, x2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( s# K3 O0 [* ~$ t) I
treatment for micropenis during early childhood. J. Pediat.,
8 U! M$ a& U7 r& X- c83: 247, 1973.9 Y( F" `! O' w% l
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' U& ]. x" V) `0 Jone therapy for penile growth. Urology, 6: 708, 1975.3 T( j6 a& c+ H
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone, U: T: i/ R2 |# ^  @8 C
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
- k) \+ p5 l/ q/ B8 zskin slices of man. J. Clin. Invest., 48: 371, 1969./ C, q# T* O  H+ G+ F$ a' \
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
! |# f. ^# W/ C$ A$ A/ ^by topical application of androgens. J.A.M.A., 191: 521, 1965.  ^6 n( V) J+ J
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) C1 O/ \; ~8 ^4 s
androgenic effect of interstitial cell tumor of the testis. J.4 b* D% H" O6 d! l) L
Urol., 104: 774, 1970.$ K& T6 T3 s4 s/ P0 u3 M0 {2 E4 u
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-1 k& [& D4 F. @( Z& y, z( h
tion in the male genitalia from birth to maturity. J. Urol., 48:
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