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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND8 R3 Z/ ~3 T% P' ~% q. S
GONADOTROPIN2 {  ?: A" {& C# D4 r# K
RICHARD C. KLUGO* AND JOSEPH C. CERNY/ X0 O3 {% m( i. `4 d8 x
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
: s! F& a$ H7 h* dABSTRACT/ B5 s5 l% S& ?3 ^
Five patients were treated with gonadotropin and topical testosterone for micropenis associated  t5 \& Y4 D% k3 R" m# @9 X
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-  S0 y9 A+ ^2 `3 s' p# S8 ^/ c
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
' I6 B5 r# N8 S  W4 h2 i8 icream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( E: c/ a3 y4 h% U$ H! N$ Qfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 q9 ?) W& E4 H0 [2 ]increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average- V# S. T& K& _9 Z' P
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 D* |  A& A5 ^/ z
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
0 J6 W& {1 S( A' fstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; a, m0 u1 q( R8 m6 wgrowth. The response appears to be greater in younger children, which is consistent with previ-3 B8 b8 [# M. L% i* A
ously published studies of age-related 5 reductase activity.4 Y& [2 e/ J. ~; @2 i$ ~' o  p1 ~; T
Children with microphallus regardless of its etiology will+ {  P6 v7 c' U4 M
require augmentation or consideration for alteration of exter-
! Y5 ]' f& ?2 S# Z% Y; Snal genitalia. In many instances urethroplasty for hypo-- u' i; l7 K2 s. E9 W
spadias is easier with previous stimulation of phallic growth., ~/ w: J6 y; \
The use of testosterone administered parenterally or topically
: e' U0 i" W2 Ohas produced effective phallic growth. 1- 3 The mechanism of
  j4 E8 Q: o1 K9 `response has been considered as local or systemic. With this: _0 M4 D! P+ Y: t
in mind we studied 5 children with microphallus for response2 _. T5 B5 u2 T4 U
to gonadotropin and to topical testosterone independently.9 [; F' ^. O* a/ m
MATERIALS AND METHODS" t- H7 N+ {* g' l8 ^, ^8 J; j
Five 46 XY male subjects between 3 and 17 years old were
; `0 s; }, F7 mevaluated for serum testosterone levels and hypothalamic
5 @* q: `/ v8 r5 n2 |: `3 M! n  H% Ofunction. Of these 5 boys 2 were considered to have Kallmann's& ]( @2 K1 |* \, E, S
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
& Y' q# C1 m! I  d, P6 E& M" Xlamic deficiency. After evaluation of response to luteinizing2 B! X0 I9 g, p8 h/ B$ r
hormone-releasing hormone these patients were treated with
; E( v3 b  r! _$ y% v1,000 units of gonadotropin weekly for 3 weeks. Six weeks7 k  ~1 m/ H$ s
after completion of gonadotropin therapy 10 per cent topical
$ i: E/ R* E; K9 p- Ntestosterone was applied to the phallus twice daily for 3 weeks.0 {5 _$ _' x6 @: {+ g" r* b7 w: B) H, t
Serum testosterone, luteinizing hormone and follicle-stimulat-+ |$ B, a$ [0 F7 H4 g
ing hormone were monitored before, during and after comple-
5 c% U2 E1 W+ a: O! a# Y( Ztion of each phase of therapy. Penile stretch length was
. S, h2 U- L0 V' Y" fobtained by measuring from the symphysis pubis to the tip of
8 }) D7 ]& {7 v# T! y6 ^the glans. Penile circumferential (girth) measurements were
7 \) J5 E2 R9 l9 j# kobtained using an orthopedic digital measuring device (see
9 M; ^- l- K  i* qfigure).2 S4 D& V# T. W# r* }: ?2 {
RESULTS8 V1 }7 z; e8 x& @
Serum testosterone increased moderately to levels between
/ D* \* ^8 v0 p$ x) v. u50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 w  Q* Y6 w6 f8 Cterone levels with topical testosterone remained near pre-
8 X2 X% y3 _% C2 Ttreatment levels (35 ng./dl.) or were elevated to similar levels
! i2 I: o( q( Q2 s* |developed after gonadotropin therapy (96 ng./dl.). Higher
' Z* w$ n+ Z' F* Q, H- t. J' t5 ~serum levels were noted in older patients (12 and 17 years old),: w+ C* v, n# z3 K  M
while lower levels persisted in younger patients (4, 8, and 10, }( z6 y" ~: X$ c/ n5 L+ Y' k
years old) (see table). Despite absence of profound alterations
/ }! a5 o2 C3 `9 L2 uof serum testosterone the topical therapy provided a greater+ F# [& s) p, |  m
Accepted for publication July 1, 1977. ·
# t$ j, x3 f& F/ W9 `Read at annual meeting of American Urological Association,1 U( a" ?! q2 z  Q* [3 S
Chicago, Illinois, April 24-28, 1977.; ~  p1 K9 W% i9 M
* Requests for reprints: Division of Urology, Henry Ford Hospital,
7 H9 @, g0 P) w2799 W. Grand Blvd., Detroit, Michigan 48202.
* L) d6 M! L  g/ J$ Jimprovement in phallic growth compared to gonadotropin.
# H# I1 D! u) h1 ]. X& D# eAverage phallic growth with gonadotropin was 14.3 per cent  y: M! T0 S4 J) m/ \, V8 E# j
increase in length and 5.0 per cent increase of girth. Topical
- C! p; D: m1 b5 G) n3 ytestosterone produced a 60.0 per cent increase of phallic length* p! g; H: k% ^7 B% `# S& w
and 52.9 per cent increase of girth (circumference). The" T+ G' E5 b! X0 Z5 {! U8 x
response to topical testosterone was greatest in children be-( F% z# e. a$ x% Q0 \' ^2 M
tween 4 and 8 years old, with a gradual decrease to age 17
: y( I# r" ~$ m; w, L9 p, tyears (see table).! ^* p: r; _: s; t- I1 B
DISCUSSION
( m$ O' z& C0 z: F* |Topical testosterone has been used effectively by other
1 \8 O3 V" t+ k: G: ^, Xclinicians but its mode of action remains controversial. Im-, e" ~: [8 V+ S1 R
mergut and associates reported an excellent growth response
! T" Z4 M$ H4 v4 E1 n  ]2 X2 Eto topical testosterone with low levels of serum testosterone,
( e# `$ d6 q9 t1 _# Y4 ssuggesting a local effect.1 Others have obtained growth re-
! i: ~- A" z4 i  q8 I/ G' nsponse with high. levels of serum testosterone after topical
9 H9 U. p, m0 dadministration, suggesting a systemic response. 3 The use of
2 e1 x  D$ y+ F- V: p5 a1 ugonadotropin to obtain levels of serum testosterone compara-
  D2 r' z5 G( i8 }! I4 X8 Gble to levels obtained with topical testosterone would seem to$ w# F0 D1 e0 S* W
provide a means to compare the relative effectiveness of& S" F/ g9 P& F2 O1 Y: h
topical testosterone to systemic testosterone effect. It cer-
' Q% U+ x; q/ X& gtainly has been established that gonadotropin as well as par-
/ K7 J# p& v- N1 o# p2 fenteral testosterone administration will produce genital3 `. U( q; X# H) `
growth. Our report shows that the growth of the phallus was
# F& l) Q9 _: r/ k4 @$ jsignificantly greater with topical applications than with go-( z( Y/ b  j% p7 F
nadotropin, particularly in children less than 10 years old.; n! f: L3 n, W9 w9 \' ?4 q3 r
The levels of serum testosterone remained similar or lower
9 n5 j1 f! o# n9 S8 q3 V+ Lthan with gonadotropin during therapy, suggesting that topi-
* @9 @3 H; v% W& ]cal application produces genital growth by its local effect as- N: B( l! ?, S# d0 x
well as its systemic effect.# N5 Z+ J2 i  v$ [7 o
Review of our patients and their growth response related to
" i) ]* Q! F( L. C7 y( W* zage shows a greater growth response at an earlier age. This is
1 R- D& p7 ^. D, a, jconsistent with the findings of Wilson and Walker, who
2 e) V( m2 }+ ?0 K& ]' zreported an increased conversion of testosterone to dihydrotes-
; k, C5 D2 V$ U/ T8 ztosterone in the foreskin of neonates and infants.4 This activ-
; Z- v2 M1 p* O# \6 jity gradually decreases with age until puberty when it ap-6 z$ t+ r  u$ {
proaches the same level of activity as peripheral skin. It may
: t: a  A$ q4 lwell be that absorption of testosterone is less when applied at
/ c0 _1 g1 G5 a) Wan earlier age as suggested by lower serum levels in children
. n6 h4 {5 a/ K1 O' d, ?less than 10 years old. This fact may be explained by the
  E* T6 T6 M( ngreater ability of phallic skin to convert testosterone to dihy-
( F; f  O* C+ _9 i& w9 K4 cdrotestosterone at this age. Conversely, serum levels in older
, U" F2 t& U! ~  Cpatients were higher, possibly because of decreased local+ [" U  O" T$ M( V
667
: ~0 v* n# j3 l" k! D$ y4 f668 KLUGO AND CERNY
; w* Q5 N/ J. P+ ~* NPt. Age
1 o  H7 U& m0 h% \" Y" k" i: b2 V# e(yrs.)8 m% n4 z8 ~( i2 t0 ~4 T9 J
Serum Testosterone Phallus (cm.) Change Length
0 t2 n0 [4 w+ w(ng./dl.) Girth x Length (%)6 q. i6 B5 H' [8 w& W3 R, y
4
7 P9 p8 ]6 [  p2 J4 |5 m2 C+ E8
$ d& y, J0 X8 u2 V4 L6 J% r) |. T10
& u1 y6 b9 l& E. E4 h# g5 ?12$ u: {  X6 Z. m$ H# c
17
" M1 F: U( t4 `$ NGonadotropin
( O  O! ?. q6 o9 ?" m71.6 2.0 X 3 16.6) _2 d) l8 _: t, x2 A' e
50.4 4.0 X 5.0 20.0% z/ n9 y( W: a5 d
22.0 4.5 X 4.0 25.0
- ^& t9 Q' a, x84.6 4.0 X 4.5 11.1
% Y0 X  R  s$ E5 N85.9 4.5 X 5.5 9.0
2 ^5 r' b- ~3 m9 ?/ J0 ^Av. 14.33 U/ j. h6 _5 T* o1 ^
40 p0 R0 m  l) K% p3 S' z! B
8
! M/ b; z$ Y# R5 a! M10/ ~3 P( F: k; z$ f, w
12
$ x4 c0 ^; Z* ~- f/ F17
0 l, K; d- V+ @) DTopical testosterone' m% M( c& P- S; w6 u: r( F5 R
34.6 4.5 X 6.5 85
9 i' L. m) z: J/ {& o/ g& Z38.8 6.0 X 8.5 70: P! q% S3 @; c- B
40.0 6.0 X 6.5 62.53 g; R" F; b- v
93.6 6.0 X 7.0 55.59 s% |! K* {' L3 m8 b
95.0 6.5 X 7.0 27.2
$ `1 B. w0 Z, M/ S# `5 j7 x- RAv. 60.0- R' t; n' f. V, t2 Z' U5 W
available testosterone. Again, emphasis should be placed on: L: n( Q6 R" m9 k3 W" h
early therapy when lower levels of testosterone appear to
" x4 g: D# g+ G1 R7 |provide the best responses. The earlier therapy is instituted  A7 v0 j" C2 |' ~2 |3 X" `, b) m# y
the more likely there will be an excellent response with low
4 m; q% R8 S) b2 L/ r& c- w; Nserum levels. Response occurs throughout adolescence as! I  c. D  b- _1 Q9 ^* ]
noted in nomograms of phallic growth. 7 The actual response
1 H$ @- }. V' u+ f. dto a given serum level of testosterone is much greater at birth# x; g  I( F6 B  o! m' x) {# W
and gradually decreases as boys reach puberty. This is most3 Y0 E- e/ n4 z! ^, L& T8 S
likely related to the conversion of testosterone to dihydrotes-
. M( @9 i7 D  L9 U0 R+ W  h8 \tosterone and correlates well with the studies of testosterone% T) N3 ]6 T- L# E! a
conversion in foreskin at various ages./ B$ c. B+ [7 p& W% y
The question arises regarding early treatment as to whether
( Z: W+ h+ m& eone might sacrifice ultimate potential growth as with acceler-
0 u7 Q; P. `% s2 Iated bone growth. The situation appears quite the reverse
4 @3 M& L, L4 _! f  W7 wwith phallic response. If the early growth period is not used" w' `; @4 i3 c- D. r3 x
when 5a reductase activity is greatest then potential growth$ C* s# s9 F$ B) z6 @& b: V+ g
may be lost. We have not observed any regression of growth
& M% l9 {' r8 M# Z. R; H6 K9 mattained with topical or gonadotropin therapy. It may well' _8 @( d( S1 T: p& ~
be that some patients will show little or no response to any  `3 e7 H0 j6 y9 @/ u
form of therapy. This would suggest a defect in the ability to
0 G  t4 D4 b. k2 Econvert testosterone to dihydrotestosterone and indicate that4 C9 h% ~3 o. D- M5 Q) ^, U
phallic and peripheral skin, and subcutaneous tissue should
- Y% c4 ~+ c! {& _/ _/ C' \be compared for 5a reductase activity.3 R& K1 Z7 {, W) [( i+ [" n
A, loop enlarges to measure penile girth in millimeters. B,
# F) S7 k1 w% ~" E; x- g- z: _1 t' yexample of penile girth computed easily and accurately.1 P: c4 m; `- [) P! ]( M
conversion of testosterone to dihydrotestosterone. It is in this
7 j4 V. w2 f" y' V+ d( }older group that others have noted high levels of serum7 p! C" J  g+ [2 B# G6 E9 f1 x
testosterone with topical application. It would also appear
! Z5 g# J$ @* e) f& l) }that phallic response during puberty is related directly to the
* J- M" y/ ^9 }) `* d4 A/ Pserum testosterone level. There also is other evidence of local
6 u- ?& I* z# N: e6 W' G5 e: V) b/ sresponse to testosterone with hair growth and with spermato-9 ]/ _) ]0 Y1 ^- I
genesis. 5• 6
7 G( \# g" @! i* x6 O1 F. RAdministration of larger doses of gonadotropin or systemic
& C. N, E4 H- }) f. ~7 V0 |2 jtestosterone, as well as topical applications that produce
, j, J1 |4 m' n: N! Vhigher levels of serum testosterone (150 to 900 ng./dl.), will
; |8 s3 a1 `; x! G: ialso produce phallic growth but risks accelerated skeletal
5 j% I& w- p9 [8 P8 Mmaturation even after stopping treatment. It would appear* z8 q3 g. _& \# @( K
that this may be avoided by topical applications of testosterone
3 z% }6 D7 R2 Z" e/ Z& Tand monitoring of serum testosterone. Even with this control; X) P9 T) r0 Q& P5 C! c0 T
the duration of our therapy did not exceed 3 weeks at any
5 H: Z: K& Y4 L2 ]) {time. It is apparent that the prepuberal male subject may
8 w* I6 e% N( e8 _$ dsuffer accelerated bone growth with testosterone levels near* f# v, M" o& P$ J
200 ng./dl. When skeletal maturation is complete the level of
1 F" ?9 _2 V- X( Q& ~3 Fserum testosterone can be maintained in the 700 to 1,300 ng./
* V  b7 S, k  R( \  B% udl. range to stimulate phallic growth and secondary sexual7 X; Z/ ]3 S! B
changes. Therefore, after skeletal maturation parenteral tes-
) f3 t9 v# w, x' {) jtosterone may be used to advantage. Before skeletal matura-8 p' o5 A0 R5 m$ N; k4 x
tion care must be taken to avoid maintaining levels of serum
, K6 D8 a* X. c2 e4 Y- V% K1 Ntestosterone more than 100 ng./dl. Low-dose gonadotropin
" z" x0 F1 q6 Mdepends upon intrinsic testicular activity and may require
6 `% u" m# n. z3 Y/ Q  Q& zprolonged administration for any response.
1 [! ?0 A1 [% M- }9 N5 V/ e; JAlternately, topical testosterone does not depend upon tes-
8 ^5 h: b, L( N' h: b! Z7 Iticular function and may provide a more constant level of4 W7 |, B; Z# r, f' ~* K7 {8 b
REFERENCES
  }& q( R0 r+ H1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,& {& i. z8 p1 i& I  k0 e& [9 F8 e
R.: The local application of testosterone cream to the prepub-
4 U9 q! t# Q# t0 f) P4 L2 Tertal phallus. J. Urol., 105: 905, 1971.
) Q8 `) x* p- l4 h. O: A2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone7 V# [( S' s5 G+ N$ j
treatment for micropenis during early childhood. J. Pediat.,
  z& P1 L  k8 L9 N5 `; _. r" V83: 247, 1973.
$ a; K$ L$ G  J5 g* B- w& }3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
1 K+ H3 g& }; `( d" X  u- Gone therapy for penile growth. Urology, 6: 708, 1975.
2 ?) L3 D6 C* ]' f1 D. x8 ?4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
7 _) H0 x( P6 a4 gto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by- L2 P- ~8 E9 F9 e( ?9 w
skin slices of man. J. Clin. Invest., 48: 371, 1969.( I" [& k9 m* a8 `
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth2 m. D3 k/ i1 Y8 K; r+ }
by topical application of androgens. J.A.M.A., 191: 521, 1965.9 ~$ c  N. }6 z. A
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local6 r' [) K4 X: b" J: k  s
androgenic effect of interstitial cell tumor of the testis. J.
1 f4 f! l6 ^* Q! q& n. O8 eUrol., 104: 774, 1970." `* z9 p. x2 I8 F1 D
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
. s# j" p6 Q5 b4 e6 ~( K- W/ {tion in the male genitalia from birth to maturity. J. Urol., 48:
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