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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 _% `6 N+ Y; J* n6 ?% K1 ZGONADOTROPIN% ~  Z2 c3 G4 {% |
RICHARD C. KLUGO* AND JOSEPH C. CERNY
. a* ^5 J6 x# kFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
0 P$ n3 P: w% ^ABSTRACT
# l" M+ O3 B( i- A$ l! C6 W& uFive patients were treated with gonadotropin and topical testosterone for micropenis associated, f: ]1 n, p+ q4 X- U
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-$ U, A/ g$ ^. }* b5 N$ C
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
+ r* e7 S6 S* h1 Mcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
; l$ g8 _0 t( R" }" Z! Efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent& S# }6 ^; u  _$ r
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average' z  @( u& g0 X' _9 S3 ?2 C' e- P
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response# Y3 S5 f/ K$ K/ q7 q' Z) p( \+ K
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 v. b4 h% f, \2 ~- }study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! W) V8 I; ~0 R4 E% E  k# ~7 L
growth. The response appears to be greater in younger children, which is consistent with previ-
7 x) S  y. d# `' G- e, }; g# Tously published studies of age-related 5 reductase activity.
+ U8 B- u9 c+ Y: SChildren with microphallus regardless of its etiology will
* M! y: P" o$ P( M; V. u! ^require augmentation or consideration for alteration of exter-; z1 Z$ X% B* h. x/ e, e
nal genitalia. In many instances urethroplasty for hypo-, |5 Z( Q8 r* ^6 d
spadias is easier with previous stimulation of phallic growth.
) _0 z: O9 Z* F7 b! i' zThe use of testosterone administered parenterally or topically% d8 r% ?! I( F; F/ n
has produced effective phallic growth. 1- 3 The mechanism of
9 b3 y7 `, n  V( t# g6 qresponse has been considered as local or systemic. With this( s" L( \6 H) a( t. N
in mind we studied 5 children with microphallus for response
5 @" O) X) x  u9 [2 m9 k" h( Rto gonadotropin and to topical testosterone independently.. v; b; a0 o, @7 ?; ^, i( z
MATERIALS AND METHODS. g, I  |" x: X: W
Five 46 XY male subjects between 3 and 17 years old were
, z1 J, {  ^( i! `* oevaluated for serum testosterone levels and hypothalamic5 R7 r& }( B; Z0 F/ T+ F3 q  p
function. Of these 5 boys 2 were considered to have Kallmann's
/ E5 \& G- Y8 o, k$ ^' Vsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-/ B! Z5 U+ F; D: T; @  O& a
lamic deficiency. After evaluation of response to luteinizing
: i( [' {2 \7 I0 ihormone-releasing hormone these patients were treated with% J2 ^8 O& o; U4 t! B- @& B
1,000 units of gonadotropin weekly for 3 weeks. Six weeks, \9 L) r% j  o+ G. O" ]! X
after completion of gonadotropin therapy 10 per cent topical
. }: |5 t# a9 T! B, etestosterone was applied to the phallus twice daily for 3 weeks.
# C1 q: T7 a, n+ C4 KSerum testosterone, luteinizing hormone and follicle-stimulat-
% R! N- u1 i' K  v) ^/ c1 fing hormone were monitored before, during and after comple-
8 l$ f5 _  E$ `3 Y6 C4 Stion of each phase of therapy. Penile stretch length was! y# C$ _# `# n8 b/ f, q+ Q8 _) e
obtained by measuring from the symphysis pubis to the tip of
. F6 c! F5 p, z9 I: y6 |the glans. Penile circumferential (girth) measurements were9 C$ x& I' v1 V$ p
obtained using an orthopedic digital measuring device (see$ s. x. E7 n  c0 f
figure).2 p  w: B! k/ I
RESULTS, q" w/ l+ m7 u) F
Serum testosterone increased moderately to levels between7 S8 }2 z# c8 i$ i' e$ I9 {& `' t3 d
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 f0 p' ^6 B7 r! w$ zterone levels with topical testosterone remained near pre-' J: F8 B8 W" f3 X& K9 z& e/ W
treatment levels (35 ng./dl.) or were elevated to similar levels
% I, E2 r1 d' }% ]. `developed after gonadotropin therapy (96 ng./dl.). Higher
- \5 P0 p* S: s* sserum levels were noted in older patients (12 and 17 years old),
# f5 u8 N) I' j! ?while lower levels persisted in younger patients (4, 8, and 10
" e/ F9 A# ]! zyears old) (see table). Despite absence of profound alterations' Q2 }% X7 Q( O- {1 Z
of serum testosterone the topical therapy provided a greater. G9 A+ d) P5 P* G: E$ d7 J2 @
Accepted for publication July 1, 1977. ·1 T6 o  T; ?7 c" a" r5 T
Read at annual meeting of American Urological Association,
- F# ]( X- @% XChicago, Illinois, April 24-28, 1977.7 {5 a& T, g9 F/ f* }5 Y
* Requests for reprints: Division of Urology, Henry Ford Hospital,9 ~% P, ~% E7 s/ i: L- h
2799 W. Grand Blvd., Detroit, Michigan 48202." H( s( M0 K% F, `
improvement in phallic growth compared to gonadotropin.
2 H9 F6 r- M: s  E: U* WAverage phallic growth with gonadotropin was 14.3 per cent
4 ]8 x* Q8 E- E& ~: _: Zincrease in length and 5.0 per cent increase of girth. Topical1 x$ H/ ~$ ]# y, i9 K8 k6 ]
testosterone produced a 60.0 per cent increase of phallic length( H8 e  s& f/ j$ A8 o
and 52.9 per cent increase of girth (circumference). The
7 N* ^: ~: ~* z5 w  Iresponse to topical testosterone was greatest in children be-
* A2 S3 ^. Z8 K1 [4 v4 U: B, _* vtween 4 and 8 years old, with a gradual decrease to age 17
9 @( x+ ]- z, o" K7 ]years (see table).
1 |' A) w' q5 |DISCUSSION% j, z5 K" Z4 S, m9 W- s4 @
Topical testosterone has been used effectively by other$ ~. Q5 e8 J& Y3 r5 h
clinicians but its mode of action remains controversial. Im-  B$ {: j( [+ e
mergut and associates reported an excellent growth response
2 P7 }8 m8 C6 ?6 @. T2 H$ jto topical testosterone with low levels of serum testosterone,7 h: X( @* K8 ~0 V( h. F
suggesting a local effect.1 Others have obtained growth re-; U+ r3 @, ]" R8 q
sponse with high. levels of serum testosterone after topical
0 [8 b( T, [0 ?administration, suggesting a systemic response. 3 The use of
0 K0 A% k5 H. Sgonadotropin to obtain levels of serum testosterone compara-
' J& s+ ]. T! i/ T/ j: cble to levels obtained with topical testosterone would seem to6 Z6 i+ ^# I1 ^6 g- b
provide a means to compare the relative effectiveness of# }9 ^. s+ b" j5 C6 d" o
topical testosterone to systemic testosterone effect. It cer-6 H& p& @: ?# T6 C' p0 R
tainly has been established that gonadotropin as well as par-
( q3 I$ \/ i7 n4 H9 lenteral testosterone administration will produce genital
! ], D2 x( L/ A  [4 }growth. Our report shows that the growth of the phallus was
, ~$ {6 v# W" R9 K2 ]significantly greater with topical applications than with go-
& j7 S8 j& j: B3 G9 Ynadotropin, particularly in children less than 10 years old.
) T6 U' Q7 P( ]7 SThe levels of serum testosterone remained similar or lower
& Q9 ]+ @* L  {! M+ |9 Pthan with gonadotropin during therapy, suggesting that topi-. G! h/ M! a/ a' S9 B: [' r: V
cal application produces genital growth by its local effect as3 x% y! d% f- t
well as its systemic effect.
; [0 _+ w8 b# v# ]0 SReview of our patients and their growth response related to
  H& c. w# [+ X* J9 M8 r4 I& [age shows a greater growth response at an earlier age. This is
( p; F3 c6 j$ n7 l; i9 Econsistent with the findings of Wilson and Walker, who" G; H. C* S1 q; z, s
reported an increased conversion of testosterone to dihydrotes-
9 k; k. w3 T0 M# j6 B, e/ ltosterone in the foreskin of neonates and infants.4 This activ-6 C  W7 i: }; `( o# V4 O6 \
ity gradually decreases with age until puberty when it ap-
1 ]  `$ e: K3 G5 Nproaches the same level of activity as peripheral skin. It may
1 h9 Y  e6 U7 v& y2 L' [well be that absorption of testosterone is less when applied at$ I. [! h# P9 y0 P
an earlier age as suggested by lower serum levels in children( ?. ^7 N7 Q' R
less than 10 years old. This fact may be explained by the9 X' ?$ |: |; \* ?/ M, o
greater ability of phallic skin to convert testosterone to dihy-
( w8 R& f* c8 ~2 y0 ~/ d$ b- j" jdrotestosterone at this age. Conversely, serum levels in older, t7 C/ d1 l) F0 u8 T* R; [! U* \
patients were higher, possibly because of decreased local
) s4 D% X0 j1 j# {9 g667
" k2 I( i9 r. g% y! q8 O8 V+ s3 U668 KLUGO AND CERNY
5 ?. p3 y' x) W* G& EPt. Age& x& y7 ^- Q- d
(yrs.)
  q3 S9 X) w: \1 n; YSerum Testosterone Phallus (cm.) Change Length
  s: b' E1 K5 b) F6 _" Y9 F(ng./dl.) Girth x Length (%)$ c+ A" g  Y& I6 t
4
# p/ p- \. e) Z1 A+ Q+ F9 \4 Q8) C4 D' J" B  h( d! x" F4 T( Y' V
109 q8 {0 e$ ~9 L8 f$ a9 i
12
# w* s! Y% p' U/ G. P" s7 ?17
+ Y3 m" V- i/ K3 ^  N- {4 ~+ fGonadotropin8 f/ y: v& y! ~3 F& L! d. j. b
71.6 2.0 X 3 16.6" j6 @, H5 c+ W" C, B9 D
50.4 4.0 X 5.0 20.0
# n$ o- W4 c" a' F3 C22.0 4.5 X 4.0 25.01 ^" X4 X% S; [" o/ X
84.6 4.0 X 4.5 11.1
& M# `$ n+ P1 Q+ S85.9 4.5 X 5.5 9.0& o' @9 R, p. A+ d5 ^0 i% l8 d
Av. 14.3$ ?8 [) d, `4 H
4+ y* f9 [6 r7 E) c4 W% m8 j, R
80 k, L7 ]# x# m
10
; s7 \( o  l5 E! E; G12
4 R3 N& W. V: w17
+ }: N! B' e: \/ E- d& eTopical testosterone: v) D( F. u. F: E/ u! X
34.6 4.5 X 6.5 85
$ z) ?2 `4 e: u/ j: w) ^+ l( G38.8 6.0 X 8.5 70) K1 |* C- q4 _& e% x- ~
40.0 6.0 X 6.5 62.5
' k8 G6 O+ X; M- ~3 |7 O93.6 6.0 X 7.0 55.5# S$ n/ f" J' c% I3 {( m4 j: b# {
95.0 6.5 X 7.0 27.2
0 z8 |# p  X3 U; vAv. 60.0
' F6 t" N1 ]4 n. d# lavailable testosterone. Again, emphasis should be placed on
4 P2 o8 s# W8 u- [( J! O& [early therapy when lower levels of testosterone appear to
. `: \8 v) s7 e+ s1 {& \4 Kprovide the best responses. The earlier therapy is instituted- W0 O# l! X' l  |' I) V4 ]/ p; R# j
the more likely there will be an excellent response with low7 ?( g2 f, _: Y  S
serum levels. Response occurs throughout adolescence as" D9 m6 E$ d, r8 J1 l: R
noted in nomograms of phallic growth. 7 The actual response0 d; c: q8 z/ K' p
to a given serum level of testosterone is much greater at birth
( E" P9 n* r) {1 {9 S' O9 o5 }and gradually decreases as boys reach puberty. This is most
: g0 {1 r& a1 T! h/ elikely related to the conversion of testosterone to dihydrotes-
/ }3 {3 S1 z4 o7 otosterone and correlates well with the studies of testosterone
6 c' U5 N' U9 H# rconversion in foreskin at various ages.
% o& f3 K5 Z2 Z; \The question arises regarding early treatment as to whether
# r, m% l+ ]5 K- n# m+ ^# _2 @# Bone might sacrifice ultimate potential growth as with acceler-* e- l! s7 r; \$ A2 T! y/ l
ated bone growth. The situation appears quite the reverse( \6 S* w5 `- \0 V- r& B/ F& k5 H, U
with phallic response. If the early growth period is not used- w+ {0 \3 `% i! f  L" p
when 5a reductase activity is greatest then potential growth0 ]! A: P$ o$ \* W0 x* Q
may be lost. We have not observed any regression of growth
/ X+ q/ y, z0 W: ?0 Yattained with topical or gonadotropin therapy. It may well, J5 z8 F6 }( t9 x6 |0 |
be that some patients will show little or no response to any  j. |% V4 `2 E0 M( b
form of therapy. This would suggest a defect in the ability to8 W  s+ V- e" D
convert testosterone to dihydrotestosterone and indicate that! g/ L* \& h" @; G
phallic and peripheral skin, and subcutaneous tissue should
6 k. B, u  u$ c% t. D9 r' t$ _be compared for 5a reductase activity.
8 g" t/ }2 d3 h& ~' v* s  jA, loop enlarges to measure penile girth in millimeters. B,
) O; V4 m( _: w) @example of penile girth computed easily and accurately./ h+ w9 s4 I# g& ^: R( N" u) ?
conversion of testosterone to dihydrotestosterone. It is in this6 o9 j2 F" N/ L
older group that others have noted high levels of serum
8 t0 d" g& G* ttestosterone with topical application. It would also appear
8 A' Q# a, R* r* cthat phallic response during puberty is related directly to the
( q3 q8 S8 H: W9 wserum testosterone level. There also is other evidence of local
+ q5 c# L+ y2 P8 t& W( ^# ]response to testosterone with hair growth and with spermato-; e2 k% s1 R0 T
genesis. 5• 62 ]2 z: S& ^1 i! ^2 O0 j. s
Administration of larger doses of gonadotropin or systemic
7 v. q7 y7 I: q5 [# ]6 z# p5 @testosterone, as well as topical applications that produce  B' w+ N4 l& f9 l* u$ y: t
higher levels of serum testosterone (150 to 900 ng./dl.), will- q! o& \9 V  Q( R2 H3 s5 Y
also produce phallic growth but risks accelerated skeletal( y; {' W% H( g3 Q: ^9 O
maturation even after stopping treatment. It would appear
9 V, u$ O* i0 l, f, |; Ythat this may be avoided by topical applications of testosterone4 ~3 z, d4 m  Z' h
and monitoring of serum testosterone. Even with this control
3 P+ W4 E' m4 ^the duration of our therapy did not exceed 3 weeks at any
. O& q5 E3 M8 {5 r) v: X. Otime. It is apparent that the prepuberal male subject may2 h& ^% y0 t9 d, w/ X
suffer accelerated bone growth with testosterone levels near2 y4 Z8 {  ^7 E! ]1 T
200 ng./dl. When skeletal maturation is complete the level of
3 f( [& J! G$ p; F4 x' Q+ z1 a1 Vserum testosterone can be maintained in the 700 to 1,300 ng./
" ^# i0 u7 }# b0 Z3 L6 y0 hdl. range to stimulate phallic growth and secondary sexual6 \, s) }, c5 @# R) l
changes. Therefore, after skeletal maturation parenteral tes-* z; q2 J1 {0 [$ g
tosterone may be used to advantage. Before skeletal matura-4 N: e' \' W* U$ G
tion care must be taken to avoid maintaining levels of serum7 Y7 T- _0 G' l, U, |
testosterone more than 100 ng./dl. Low-dose gonadotropin
* f: k& |; w4 u! Cdepends upon intrinsic testicular activity and may require
3 b4 \& i5 ]' N& {% J7 P6 ]  @prolonged administration for any response.
( c3 y4 w1 h& S! ^Alternately, topical testosterone does not depend upon tes-
8 ?+ Z! _: n5 Z+ b. ~2 dticular function and may provide a more constant level of
, ?( \: O: |3 J+ r2 [REFERENCES
# k1 B4 L0 s/ d# {0 z0 S$ W- d: A% D1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
9 G8 Z) P/ _" r7 q$ dR.: The local application of testosterone cream to the prepub-9 A3 v1 \/ d7 `( [2 A
ertal phallus. J. Urol., 105: 905, 1971.! m& g8 F9 m8 @) ?' M( G
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
( i/ J0 d! r% ^7 r' G$ @& dtreatment for micropenis during early childhood. J. Pediat.,
' P( r. v" I% b+ P! }5 ]- W) Z83: 247, 1973.
& L7 \$ ]8 h8 D8 K6 D( }3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
9 J. F& d( M8 \: ]4 M$ xone therapy for penile growth. Urology, 6: 708, 1975.
/ [6 S) W. F1 j7 ^2 G& G4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone0 c! ?! S, l' h% y' s
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by, o# B- v: o' H! X6 c5 |
skin slices of man. J. Clin. Invest., 48: 371, 1969.) h3 {4 c* I- \) ^+ I2 z- q6 Z! ]
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
2 D& @2 @3 M& a, F; a; mby topical application of androgens. J.A.M.A., 191: 521, 1965.
% x7 w7 k" R9 p' A( ?0 j6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) V  V" }6 b  |( Z5 e: H
androgenic effect of interstitial cell tumor of the testis. J.4 J4 O* Q) K; I% U; q
Urol., 104: 774, 1970.# W! k2 }! M. c# ]% n
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-, o& T0 t2 D% H2 R! {
tion in the male genitalia from birth to maturity. J. Urol., 48:
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