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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
; B, N- Y0 o2 U6 @  u" e7 {! }GONADOTROPIN  m, a9 O' |7 t. w6 A9 o
RICHARD C. KLUGO* AND JOSEPH C. CERNY3 L! ?* m2 X" ]- u1 n& g* _- ^$ C
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
' H" n8 A' V( P% p( ~9 p: QABSTRACT* k% m2 F* P& ]
Five patients were treated with gonadotropin and topical testosterone for micropenis associated6 k& p& T+ H& N- s+ X
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
5 a- b( K% e" h) `! etropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
* j9 K& Q7 ^7 n, y- v- B: Ecream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
3 @, M, \  N& v1 Pfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
/ S* y, v& z8 J) q8 k, Z$ h- Pincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average: F/ Q( s3 `' t  N
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response2 Y$ z0 F8 X4 v9 W- L  W/ o, K: a
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 X5 q, Q4 R2 K; P1 Y8 D5 o6 Fstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile7 O. p2 w( P' Y* P- {. R+ _
growth. The response appears to be greater in younger children, which is consistent with previ-
9 G( X7 F3 x+ e6 J+ [" b" g6 qously published studies of age-related 5 reductase activity.
9 q5 t  j6 _5 [! f. z: O) [Children with microphallus regardless of its etiology will
6 F9 a5 x- B! `# M9 O: W% C& |1 Grequire augmentation or consideration for alteration of exter-5 ]; r# ?/ \- d, n
nal genitalia. In many instances urethroplasty for hypo-/ a$ ~! j% X/ A
spadias is easier with previous stimulation of phallic growth.
1 S8 |5 m% V& e# A" K6 D0 X0 B3 mThe use of testosterone administered parenterally or topically
; g2 F5 S$ a3 o' G- ~1 j( Hhas produced effective phallic growth. 1- 3 The mechanism of8 Z0 s+ P4 e- L9 m. f
response has been considered as local or systemic. With this1 l: x: ~- d; \7 W1 j3 |( y
in mind we studied 5 children with microphallus for response
' n- n6 U( A9 g* G1 f8 jto gonadotropin and to topical testosterone independently.
4 B8 J/ ?5 i1 u. ]$ C2 bMATERIALS AND METHODS
6 R, r) W5 ?; j9 Y1 f6 ?" ~5 M. f0 qFive 46 XY male subjects between 3 and 17 years old were
( S; q& y4 I( d! q- Q  }evaluated for serum testosterone levels and hypothalamic, O% v, m* \, }8 u+ R. ?
function. Of these 5 boys 2 were considered to have Kallmann's
+ w) \' o) [* Q. t" Tsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
0 D) {  Q8 ?% Xlamic deficiency. After evaluation of response to luteinizing0 l) D5 z  ~& O  f
hormone-releasing hormone these patients were treated with
2 l! C* o4 O+ R% i! P1 [7 y1,000 units of gonadotropin weekly for 3 weeks. Six weeks: _1 e$ K& I; _
after completion of gonadotropin therapy 10 per cent topical
; T5 g% M9 m8 p( L2 E- h: Qtestosterone was applied to the phallus twice daily for 3 weeks.* _4 p: E# N1 X, a. z% w
Serum testosterone, luteinizing hormone and follicle-stimulat-  A1 S% p2 D9 i
ing hormone were monitored before, during and after comple-! m$ e! y. X& D) ?1 g7 f: ?
tion of each phase of therapy. Penile stretch length was
, E' V* Y1 D* w/ W; |: aobtained by measuring from the symphysis pubis to the tip of
$ \% m8 a# Z0 E7 mthe glans. Penile circumferential (girth) measurements were' V4 t' M& J3 X
obtained using an orthopedic digital measuring device (see
) X% |) V# Y& e. ~0 Z) F$ _' gfigure).1 j% u9 b6 r# a2 o- W( ^/ `
RESULTS
5 k" P# q8 }1 XSerum testosterone increased moderately to levels between4 E5 E$ {$ b7 d% p  @9 N3 A
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-: v" N+ O4 a$ R3 Z  k" T3 @2 i, C* H
terone levels with topical testosterone remained near pre-( z1 c) u& q) v. [& Y3 G
treatment levels (35 ng./dl.) or were elevated to similar levels
0 u4 r/ y9 e9 {. q9 A' Gdeveloped after gonadotropin therapy (96 ng./dl.). Higher
5 _0 H9 b5 [% D* \- Zserum levels were noted in older patients (12 and 17 years old),, u% J  B. T- r$ J. h2 L+ S
while lower levels persisted in younger patients (4, 8, and 106 j! K( _8 G6 I
years old) (see table). Despite absence of profound alterations; S8 u  A: K+ p! z
of serum testosterone the topical therapy provided a greater
$ k8 Z+ a: o" e9 p# r( \Accepted for publication July 1, 1977. ·
) u: s) l( r% @: [4 x! hRead at annual meeting of American Urological Association,- c5 v. B  s! Z5 P/ B/ q
Chicago, Illinois, April 24-28, 1977.
* u5 \' J/ d  i  `* Requests for reprints: Division of Urology, Henry Ford Hospital,
; }0 m! X' F3 M2799 W. Grand Blvd., Detroit, Michigan 48202.1 r2 v" n0 U1 b7 k  T. [) I
improvement in phallic growth compared to gonadotropin.
3 D4 b, f: W: F1 M$ r' e- }Average phallic growth with gonadotropin was 14.3 per cent; D( @, v* g5 a2 T# v: d
increase in length and 5.0 per cent increase of girth. Topical; ~5 J; \6 s+ N/ p
testosterone produced a 60.0 per cent increase of phallic length
6 g0 B, S& Y2 yand 52.9 per cent increase of girth (circumference). The
3 i! y9 I6 G) B) Uresponse to topical testosterone was greatest in children be-* Z, ~+ V, f2 P( [7 @& N0 T* c
tween 4 and 8 years old, with a gradual decrease to age 17, ^1 u. R3 Z/ y( a3 Z
years (see table).
8 B$ Z' ~0 ?, g/ X; H# d  VDISCUSSION3 {9 ^  d0 w* J! X
Topical testosterone has been used effectively by other6 h( j" V5 _3 {/ s5 H& X6 m
clinicians but its mode of action remains controversial. Im-
2 [- q+ f, T. I, P. Mmergut and associates reported an excellent growth response) S; |) @/ n$ z& g$ g# e& O9 ~
to topical testosterone with low levels of serum testosterone,
7 a  Y4 d1 M+ Hsuggesting a local effect.1 Others have obtained growth re-4 I* P# X4 r' ?1 e9 J
sponse with high. levels of serum testosterone after topical/ a' F0 C6 J3 H( y
administration, suggesting a systemic response. 3 The use of6 o- N* h3 h4 V  b# b% n6 ?
gonadotropin to obtain levels of serum testosterone compara-
& Q& H7 {3 W% V, ?" N( Bble to levels obtained with topical testosterone would seem to; b0 E5 j4 L$ p4 S: L0 G+ a) Q# I4 C
provide a means to compare the relative effectiveness of' i$ [+ ~2 k4 l% g! p/ U
topical testosterone to systemic testosterone effect. It cer-8 a1 e+ Y: }5 T- B/ T
tainly has been established that gonadotropin as well as par-
7 F  F# G9 S: @1 w  tenteral testosterone administration will produce genital
+ m6 T0 U" L; q& Rgrowth. Our report shows that the growth of the phallus was
( X' y) f( z: k" n. M8 K! F0 Fsignificantly greater with topical applications than with go-
8 j) k6 J1 J: t5 N$ {nadotropin, particularly in children less than 10 years old.! Y) ~6 B+ T" k* z  b- p% a
The levels of serum testosterone remained similar or lower
- f" T1 G  c7 Bthan with gonadotropin during therapy, suggesting that topi-2 d5 U5 Z" u$ o- G5 h3 ~# d
cal application produces genital growth by its local effect as6 x1 N/ `- l+ M. K
well as its systemic effect.( P0 H4 O9 K8 e- W% S( R2 c
Review of our patients and their growth response related to
* X* j! e2 V  m9 b6 e, p6 _0 p  Cage shows a greater growth response at an earlier age. This is
3 e8 W/ W. t9 J# dconsistent with the findings of Wilson and Walker, who
7 d# f% A+ g) O+ ?9 E- lreported an increased conversion of testosterone to dihydrotes-5 J' J7 N/ P7 `7 ]5 }
tosterone in the foreskin of neonates and infants.4 This activ-/ F  c0 P- @' E8 _. _' {: K5 f
ity gradually decreases with age until puberty when it ap-
7 t# c% ]- u5 m" E0 ^) tproaches the same level of activity as peripheral skin. It may
0 O9 T- F1 A9 \/ gwell be that absorption of testosterone is less when applied at2 _) i. \- ~: [: {8 @0 d
an earlier age as suggested by lower serum levels in children
& ?, T' H! u+ \0 \) h' bless than 10 years old. This fact may be explained by the( ]8 j: B9 P% Z1 h1 [" y' y  K
greater ability of phallic skin to convert testosterone to dihy-
6 ^/ K3 R+ x& u) Q  Ndrotestosterone at this age. Conversely, serum levels in older" b3 \; A4 b4 F9 t
patients were higher, possibly because of decreased local# ?+ s( M. `' M! I6 W; z
667) H! Y. y. J% F) D) ?  ?) @
668 KLUGO AND CERNY
) D7 P& E  T4 P1 r1 uPt. Age
$ k: B0 e0 j$ x& r7 G9 ^(yrs.)5 @! P' t- ]3 F. @% r! L
Serum Testosterone Phallus (cm.) Change Length- V& O2 f( }/ D3 r
(ng./dl.) Girth x Length (%)
2 E5 ^7 ?' I2 }$ u- a45 l- [' M: [5 q! Q" u: g
8& [3 i$ K4 t: {( X, L+ R
10
3 m- f! Y4 x/ _12& R$ [" _# }4 m( m' `
17
! H0 S; b0 I+ [: G* N( \Gonadotropin
; E$ h; c! L# u" m# J71.6 2.0 X 3 16.6
8 U* K) n6 E' \( T50.4 4.0 X 5.0 20.0
2 x, r- f0 p" R8 Z$ F' u, ^2 K% j. Q22.0 4.5 X 4.0 25.0
6 b0 k4 b$ O' ]  K9 J# Q5 ^84.6 4.0 X 4.5 11.1
& V4 G0 V7 _' s6 P0 A! V85.9 4.5 X 5.5 9.0
- q: M0 @; t) S3 _9 {Av. 14.3
6 x" {* t. {; M9 d4
5 m* P  B/ |3 _8 C' s81 b2 k9 |8 n$ n$ L
10
3 Z& I& [2 F9 x12
7 y+ p: D: Z, a4 {9 c" F# G/ M! y! h17
% j* d% L3 Q" S0 _( A+ [+ ?9 j  kTopical testosterone# T, X! A3 L6 R- M: }5 U4 X( Z: @3 ?
34.6 4.5 X 6.5 85' j, B* j0 e+ |! q% E) l  k
38.8 6.0 X 8.5 70$ e3 t9 Q* Q& P- N
40.0 6.0 X 6.5 62.5
$ B3 M+ @! H4 f  }) M93.6 6.0 X 7.0 55.5, j: d5 u! p/ i6 n8 ]$ q
95.0 6.5 X 7.0 27.2
) k9 I5 K5 I# a: s4 {Av. 60.0- \9 f0 R9 b( A/ a+ I( @
available testosterone. Again, emphasis should be placed on
5 [- k) \3 Z9 xearly therapy when lower levels of testosterone appear to7 t3 O8 W& ^7 M2 n
provide the best responses. The earlier therapy is instituted4 B- g# r$ W! G, ~7 V: ~6 F5 r& P
the more likely there will be an excellent response with low$ c; U& o" _" p* y# b" c
serum levels. Response occurs throughout adolescence as
0 P4 ]- S" S* bnoted in nomograms of phallic growth. 7 The actual response
4 m+ z. B. G! A* B/ T& tto a given serum level of testosterone is much greater at birth; H2 R0 r% \+ H4 ^" |5 ^  ^7 @
and gradually decreases as boys reach puberty. This is most; j! w" m2 |% d* k
likely related to the conversion of testosterone to dihydrotes-
  g, _$ y) R" u/ ^" R% G2 itosterone and correlates well with the studies of testosterone. h: B6 P/ ?( a& O$ N, A
conversion in foreskin at various ages.
( v7 g. d7 n) n6 d5 D  AThe question arises regarding early treatment as to whether
1 M7 d$ X* A  M. f, E. O- Ione might sacrifice ultimate potential growth as with acceler-0 H0 v7 b! F5 ?" k$ a8 g8 G. N
ated bone growth. The situation appears quite the reverse1 f& n3 h, ]$ l; i3 x2 Z; E7 S
with phallic response. If the early growth period is not used" o. @/ T% S7 \( ~) w
when 5a reductase activity is greatest then potential growth( \2 k+ x) {9 t
may be lost. We have not observed any regression of growth
9 b) `6 X% s8 A( ?3 D' aattained with topical or gonadotropin therapy. It may well1 ~. V# i0 G/ j5 |
be that some patients will show little or no response to any
6 x0 d9 g3 R' xform of therapy. This would suggest a defect in the ability to
; A" f' D6 [. L9 t' g+ jconvert testosterone to dihydrotestosterone and indicate that# j" r% p3 m! t/ _. X( c, |7 t4 X
phallic and peripheral skin, and subcutaneous tissue should+ R' _% z" p6 C1 [# Y
be compared for 5a reductase activity.
: @# t8 w3 w) W. W; H0 iA, loop enlarges to measure penile girth in millimeters. B,
' ~+ }" {0 e; d6 ~! R; {4 {% G: g( J( Mexample of penile girth computed easily and accurately.- [( z+ [5 F; S/ L5 R
conversion of testosterone to dihydrotestosterone. It is in this
  ^3 t% j& @5 w. r& ~8 Q9 polder group that others have noted high levels of serum9 |9 ]  E% t  P, f% t
testosterone with topical application. It would also appear3 c" _1 M0 F2 a8 t
that phallic response during puberty is related directly to the# S6 ]1 [3 Y/ W3 G* H
serum testosterone level. There also is other evidence of local, B8 c. i  W3 B- B; c0 R
response to testosterone with hair growth and with spermato-6 M  X3 M: c' V9 p8 j7 j
genesis. 5• 6
3 l+ {% e( C3 E  q7 ]" n+ BAdministration of larger doses of gonadotropin or systemic: a5 |7 y+ h' v& q% R
testosterone, as well as topical applications that produce5 j# \9 d/ N7 }0 P& S: ^* c
higher levels of serum testosterone (150 to 900 ng./dl.), will
7 H  ^  P, C5 u7 o' u* @# Halso produce phallic growth but risks accelerated skeletal( j: E1 Z% ^- ]
maturation even after stopping treatment. It would appear! t, @6 x- v, z" a- u
that this may be avoided by topical applications of testosterone
0 }7 E4 w5 e6 U/ sand monitoring of serum testosterone. Even with this control9 O: F$ v2 m& E( i1 v, o
the duration of our therapy did not exceed 3 weeks at any
0 J) |7 d1 a% ktime. It is apparent that the prepuberal male subject may
; V3 ?6 t/ x' Zsuffer accelerated bone growth with testosterone levels near, p8 Y; b4 G0 @0 t
200 ng./dl. When skeletal maturation is complete the level of
8 g) U6 ?# P7 W- o& B) [0 G7 @+ w" Bserum testosterone can be maintained in the 700 to 1,300 ng./
' q0 n5 ^& h; G! F: sdl. range to stimulate phallic growth and secondary sexual
' _% Y9 P. Q$ bchanges. Therefore, after skeletal maturation parenteral tes-& J8 {; A; ~2 Y" b# P  {* F4 B
tosterone may be used to advantage. Before skeletal matura-0 i+ O- x$ G8 p% C& J
tion care must be taken to avoid maintaining levels of serum" }: |6 R0 R. Z' x9 \2 I; f) ?
testosterone more than 100 ng./dl. Low-dose gonadotropin
% d$ ^4 E: ?: i  n' x0 X. ]depends upon intrinsic testicular activity and may require
& {* R+ w, Y, f# M4 pprolonged administration for any response.
0 ~% `0 u3 k2 |# _+ ^. H% DAlternately, topical testosterone does not depend upon tes-
7 e5 X+ c5 e/ Nticular function and may provide a more constant level of
+ M3 \/ D( J7 k" ^REFERENCES
- v- F8 X% U& G: {) f" ?6 r1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; _( r4 G" X: T: o
R.: The local application of testosterone cream to the prepub-9 ~- q0 p6 k. n
ertal phallus. J. Urol., 105: 905, 1971.
( ~6 R+ m& ]2 J6 ~& q2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone+ ~$ ?% @2 L* G9 w* l
treatment for micropenis during early childhood. J. Pediat.,
) R1 M" Y" z, p, V1 ~5 I83: 247, 1973.+ Z: l  r8 l2 |, @5 g) ?4 J
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
2 B; ]7 r7 E3 p: d9 }one therapy for penile growth. Urology, 6: 708, 1975.4 r/ K* U/ }0 Y6 o) H: j
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 _0 ]6 i* A8 h% k/ K- Q! A! ^8 @
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
2 i8 e3 B  \( G' p# x2 mskin slices of man. J. Clin. Invest., 48: 371, 1969.* }- R: R0 {+ o5 O
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
* i+ n& V; d7 P4 j  o$ zby topical application of androgens. J.A.M.A., 191: 521, 1965.* `! g! L' E# P( O
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ U+ E7 D8 V% g+ [# K
androgenic effect of interstitial cell tumor of the testis. J.  a7 H' G) C" m$ E- O
Urol., 104: 774, 1970.1 e6 O0 K/ ?" O' e" F
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-) t3 N& C/ [- e1 g' f
tion in the male genitalia from birth to maturity. J. Urol., 48:
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