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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND: b/ [: F% P# }1 B4 ?) |% O" d& ]
GONADOTROPIN+ {2 N) f* {0 A# V! Y+ x% M
RICHARD C. KLUGO* AND JOSEPH C. CERNY: I% Q6 f; Q4 m. Y& R9 N8 I
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan, I/ g  r5 }/ f" V. w2 T& E
ABSTRACT8 D# P) q" U0 X& H: a
Five patients were treated with gonadotropin and topical testosterone for micropenis associated4 }5 `7 T: j5 U$ M0 H, e( w
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
$ P9 x- J* S+ r- P; S5 L( T2 ?tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
: f4 v" y/ x6 d# q6 r; A3 Icream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
1 R% x, }, K/ g6 |3 yfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
2 n# Q3 q0 A5 D" j+ Z% z$ lincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
) J( n6 h0 G8 |5 p5 _increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
& Y1 n6 l/ `4 ^  r- z! Qoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
4 x' e9 I- V% c# u+ S* @study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile8 d$ F8 P/ `, e
growth. The response appears to be greater in younger children, which is consistent with previ-
/ M9 `5 o- x: Q, `; [7 Q* B& v1 Kously published studies of age-related 5 reductase activity.
4 M1 a4 x( ^  n+ }8 V$ X& |! N& jChildren with microphallus regardless of its etiology will# z3 s% p) j# N' R  M# g- B( l, _- ~
require augmentation or consideration for alteration of exter-
; {. N: `1 B9 m5 Q- Unal genitalia. In many instances urethroplasty for hypo-  O* [4 B6 s% t) p6 D1 n2 }
spadias is easier with previous stimulation of phallic growth.
5 Y" g& Z& t# @) NThe use of testosterone administered parenterally or topically0 b4 x& Y# \. d2 {5 F
has produced effective phallic growth. 1- 3 The mechanism of4 A4 I% ~. o; d/ P& e
response has been considered as local or systemic. With this# {" |) j" M" x: ]; I5 T
in mind we studied 5 children with microphallus for response
8 ]- h0 z. @# Z# ]4 |; n- w) \, pto gonadotropin and to topical testosterone independently.3 }5 I! I2 Z  p( v% d
MATERIALS AND METHODS% x/ G! T+ w- y4 j
Five 46 XY male subjects between 3 and 17 years old were. X) d) z, T  Y. I" N' f7 E
evaluated for serum testosterone levels and hypothalamic4 _2 r9 ]9 v9 Z4 l
function. Of these 5 boys 2 were considered to have Kallmann's
; D5 R- w! L* G- L  nsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-4 w, s8 C. O+ \
lamic deficiency. After evaluation of response to luteinizing6 ^" o0 N5 g  `
hormone-releasing hormone these patients were treated with7 l. X  V# I! G& y4 _8 c4 X
1,000 units of gonadotropin weekly for 3 weeks. Six weeks/ C  t) M7 M; C- r- G0 E8 k9 V
after completion of gonadotropin therapy 10 per cent topical
/ o) N, ]5 x& T9 f7 r4 c1 mtestosterone was applied to the phallus twice daily for 3 weeks.3 [$ J0 Q# `  O. z! J. z
Serum testosterone, luteinizing hormone and follicle-stimulat-) Q( u" B! }$ r- d
ing hormone were monitored before, during and after comple-
( D5 C/ M; p: @- {6 btion of each phase of therapy. Penile stretch length was
( F: e; H# c4 }: n  Jobtained by measuring from the symphysis pubis to the tip of1 t/ ~5 a' l2 k$ u: _4 G
the glans. Penile circumferential (girth) measurements were
! ?. A8 Q6 Q* S: j& Sobtained using an orthopedic digital measuring device (see
8 r; ]# A- s# Q. l6 t$ q/ W  y* Z( Jfigure).2 _1 r8 V, O$ |1 V3 b
RESULTS
$ {3 O5 d6 m" j2 {6 TSerum testosterone increased moderately to levels between
' `' V, ]: Y+ N7 Y5 h9 J50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
9 L4 A: a+ L1 B2 w5 Z& [terone levels with topical testosterone remained near pre-
5 [; Z& o1 s3 G7 V& Wtreatment levels (35 ng./dl.) or were elevated to similar levels
) `0 a; `6 L/ r0 i5 j/ H) {6 edeveloped after gonadotropin therapy (96 ng./dl.). Higher
, A) r( {7 P6 M% k, o5 Z2 G) l6 jserum levels were noted in older patients (12 and 17 years old),9 P2 v" a$ b8 K! `: C; [' N
while lower levels persisted in younger patients (4, 8, and 10
) Q3 [& b' C: ^years old) (see table). Despite absence of profound alterations
) Z/ i; I  R$ U) Oof serum testosterone the topical therapy provided a greater
: t  W9 I  W( E- `% v+ {/ r1 CAccepted for publication July 1, 1977. ·- W+ K& j$ j. M5 F% _* F, q/ z6 K
Read at annual meeting of American Urological Association,
( [3 E3 k+ E6 q3 }$ l8 z! s2 tChicago, Illinois, April 24-28, 1977.
- G9 U* g0 E, y" U- ~( A4 b& l6 I* Requests for reprints: Division of Urology, Henry Ford Hospital,
: n) v/ V( w6 f2799 W. Grand Blvd., Detroit, Michigan 48202.
: ~& Y; r  _& G( c4 a* V$ }improvement in phallic growth compared to gonadotropin.
1 p; z* R$ T" N" T  I" AAverage phallic growth with gonadotropin was 14.3 per cent3 r# I/ |, v. i4 p2 o  T( E
increase in length and 5.0 per cent increase of girth. Topical
- O' `; a' ^2 J: ^* Stestosterone produced a 60.0 per cent increase of phallic length
( w- |) h8 e' S4 T+ m+ B  dand 52.9 per cent increase of girth (circumference). The
# V; J$ }) @0 w( v- k1 Tresponse to topical testosterone was greatest in children be-
& g6 G5 b/ O: R, l6 j) ^tween 4 and 8 years old, with a gradual decrease to age 17
* V4 O; F& a/ o8 P4 Ayears (see table).3 G+ r# F( L' u% Y# |6 K
DISCUSSION$ ]# E7 ?2 y7 ^2 s
Topical testosterone has been used effectively by other4 Q% H3 d( Q1 w6 b* D
clinicians but its mode of action remains controversial. Im-) K: k4 Z9 |$ a: d/ B6 T
mergut and associates reported an excellent growth response
8 ]( G# J- O' a) V0 E& D- w6 t, ?* ^: A3 Fto topical testosterone with low levels of serum testosterone,) |) n! M4 E& o# L: _: ~3 Q. b
suggesting a local effect.1 Others have obtained growth re-
! O; y) _; A: i; ]% I, hsponse with high. levels of serum testosterone after topical
# Q+ l6 ]- k0 o# H  E/ g1 U/ S  H0 k) eadministration, suggesting a systemic response. 3 The use of
) U+ t! c" M) A6 v$ G  e' v7 ~gonadotropin to obtain levels of serum testosterone compara-
$ p8 P' T1 Y' }; ^+ z7 Z" sble to levels obtained with topical testosterone would seem to, o6 P( S. {% }" K
provide a means to compare the relative effectiveness of6 \! R+ B/ d0 y7 S$ T' T
topical testosterone to systemic testosterone effect. It cer-
( J; y/ W5 t9 F3 w8 c' ytainly has been established that gonadotropin as well as par-
' N+ J, n! a  M! ^enteral testosterone administration will produce genital
. X" p% k- k6 L, agrowth. Our report shows that the growth of the phallus was& g& P! e7 s6 M+ ~. q6 Q9 v5 D
significantly greater with topical applications than with go-* l) V% D) S/ V
nadotropin, particularly in children less than 10 years old.
& [  m! M/ b; i; _# [0 b3 K* c2 G+ wThe levels of serum testosterone remained similar or lower
+ p4 e% N: i" J1 N- p3 \7 _than with gonadotropin during therapy, suggesting that topi-, S% R/ v* g$ s/ z
cal application produces genital growth by its local effect as
" g& h+ L3 l% p! a# Swell as its systemic effect.
" N" L! T6 X. s' wReview of our patients and their growth response related to( `; l0 ~+ ~) i
age shows a greater growth response at an earlier age. This is/ ], e, w& N# q8 P9 ~, Q
consistent with the findings of Wilson and Walker, who
9 J% f( Q6 M# o, t# k; F2 k4 Oreported an increased conversion of testosterone to dihydrotes-& {! q# z0 E6 ]+ T! Y0 W
tosterone in the foreskin of neonates and infants.4 This activ-
4 S) V9 b; O! ~; t4 L  l2 rity gradually decreases with age until puberty when it ap-
( z& b( s5 T- Q% |/ f% ?proaches the same level of activity as peripheral skin. It may* n  n4 C$ y# I3 A
well be that absorption of testosterone is less when applied at1 Z5 b7 M% t2 I) ^
an earlier age as suggested by lower serum levels in children* \( Z$ k) A) F
less than 10 years old. This fact may be explained by the; s! X$ X& h$ C0 x
greater ability of phallic skin to convert testosterone to dihy-
: H" Z0 |$ S3 I( S% fdrotestosterone at this age. Conversely, serum levels in older. e0 x2 x4 w, C& s. s
patients were higher, possibly because of decreased local; N& [- j: d& m( J
667
1 {0 e0 i) Q& A668 KLUGO AND CERNY# ?8 M6 A, x) x* M9 z8 ]6 \' B, s
Pt. Age& w7 D7 N! S; k7 t, a
(yrs.)% G, m. s2 i6 F, J
Serum Testosterone Phallus (cm.) Change Length1 ?0 T! [2 e3 @0 s. ^9 n8 S
(ng./dl.) Girth x Length (%)
# W' P3 O; f/ J4 l+ r8 Z  }+ q6 b4  S( S2 q( N* B4 D
8
2 I/ W  L: J6 A103 \* n* q1 U7 r3 H+ Z: {
12  k6 v( a; C- l6 z! ^( T
17
8 J1 d0 C) t: L1 t" \: X0 f4 qGonadotropin" }8 Q* @. }4 y( m8 [6 A! S
71.6 2.0 X 3 16.6
: `! _* o5 p. O* _6 `$ h' A$ ~50.4 4.0 X 5.0 20.09 l* B1 i4 C6 c, Y- F
22.0 4.5 X 4.0 25.0$ T' d4 ~$ j, x9 L
84.6 4.0 X 4.5 11.1
2 v% C, n8 X) f- _" P8 `0 d! v85.9 4.5 X 5.5 9.08 _6 C2 F4 T2 L6 t
Av. 14.32 s$ a; K1 J7 Q- }( F
4: _' A5 g% C3 z( x4 x
8
; ^- g- u  |3 q5 J& W100 J' {7 [" [9 H, h0 Z4 s6 b
12$ o  D! w' T- ~7 R- u9 v
173 M, c7 Z. B, y4 ~7 g5 ^$ E
Topical testosterone
( Y9 s+ Q0 H3 d$ }% \' y* q34.6 4.5 X 6.5 85
& K3 \# W6 n+ g% S7 K. O" n38.8 6.0 X 8.5 70
$ N8 S( S) [3 P; ]40.0 6.0 X 6.5 62.5
; T" x5 I+ E, j2 V/ ~! b. v93.6 6.0 X 7.0 55.5
6 U7 b2 M2 B4 Y2 p% |8 L95.0 6.5 X 7.0 27.2
9 S1 r! h+ Q% Y  o- ~5 DAv. 60.0
8 t% a5 z5 B* |available testosterone. Again, emphasis should be placed on
7 V, G$ {- m2 M* H2 e$ }" searly therapy when lower levels of testosterone appear to! K+ c  z8 G) d7 b7 ^1 }
provide the best responses. The earlier therapy is instituted
- G- `3 O2 l  B; u% bthe more likely there will be an excellent response with low) y1 _$ t0 V5 B3 P; ?
serum levels. Response occurs throughout adolescence as0 @; Q' P! ]3 ^1 [* I; v- B
noted in nomograms of phallic growth. 7 The actual response
! b/ S7 ]$ x. U. E  F2 g, X5 ato a given serum level of testosterone is much greater at birth  ~3 d3 f+ `1 y$ u5 {- i
and gradually decreases as boys reach puberty. This is most
, m8 P& Q( p) |9 z3 |likely related to the conversion of testosterone to dihydrotes-
& G' d9 d# z  v/ u* F3 G. atosterone and correlates well with the studies of testosterone
' ]" x! W' b* R: o' h/ s' j. n1 Econversion in foreskin at various ages.5 D6 f7 J) T+ j) r) ]" \4 h- W4 Z
The question arises regarding early treatment as to whether" J5 J1 Z: t# b$ o" @# Q
one might sacrifice ultimate potential growth as with acceler-
+ J+ f' ~) Y5 ]7 fated bone growth. The situation appears quite the reverse
4 i0 m) {! }# C2 Y+ bwith phallic response. If the early growth period is not used/ M% c2 p4 }, C5 K3 w
when 5a reductase activity is greatest then potential growth- F' t9 M$ P, K* l  l
may be lost. We have not observed any regression of growth( {. ]8 o: ~: E/ W  B, i
attained with topical or gonadotropin therapy. It may well
0 z/ f% i$ v% k2 J* [* j$ Ybe that some patients will show little or no response to any  `, U" `+ y( O6 d1 q; ~
form of therapy. This would suggest a defect in the ability to2 C2 G3 q3 h; z
convert testosterone to dihydrotestosterone and indicate that
  W" S% P0 }( P* c2 v; Bphallic and peripheral skin, and subcutaneous tissue should
" m' o9 R( o: b! q/ q: gbe compared for 5a reductase activity.) h2 h, j# i! W, H
A, loop enlarges to measure penile girth in millimeters. B,
6 ~" \! a0 P' \' Z, P) dexample of penile girth computed easily and accurately.( J# c- w* c" t1 s0 e2 ?8 }
conversion of testosterone to dihydrotestosterone. It is in this
0 ]5 I0 W+ h# folder group that others have noted high levels of serum$ L# T6 D, Z  ~) e' B
testosterone with topical application. It would also appear
% C) Y. v; \/ f; A+ j1 u) i7 h4 Ythat phallic response during puberty is related directly to the
" I" z8 F7 G' ?& k* ]7 d  tserum testosterone level. There also is other evidence of local3 ~- i: Q6 s3 t, N, F7 q  A
response to testosterone with hair growth and with spermato-
/ a7 r! M. O$ D1 E0 f7 ?9 \* pgenesis. 5• 60 w& O, ~: e" x
Administration of larger doses of gonadotropin or systemic' M8 \) J0 N& X4 I: p
testosterone, as well as topical applications that produce  U' W8 A, R$ P4 P$ r2 r" k
higher levels of serum testosterone (150 to 900 ng./dl.), will
7 Z$ s/ ^, i$ I" f8 Z$ i7 `/ ?also produce phallic growth but risks accelerated skeletal2 f. s+ s1 E4 x4 W
maturation even after stopping treatment. It would appear
, s& s2 }6 C) K2 [that this may be avoided by topical applications of testosterone, k6 J+ H* A5 A3 f, e9 ^
and monitoring of serum testosterone. Even with this control
/ V) Y! ^1 i6 T8 g& S$ tthe duration of our therapy did not exceed 3 weeks at any9 d4 y+ M. [% e+ ~( a1 q/ h
time. It is apparent that the prepuberal male subject may6 N( q. k4 x/ C; I6 [8 C$ E' @$ i
suffer accelerated bone growth with testosterone levels near1 g8 A, o0 R: Y* u2 U3 K. W
200 ng./dl. When skeletal maturation is complete the level of' l; p" u2 W, c
serum testosterone can be maintained in the 700 to 1,300 ng./
9 }4 |+ i7 H9 z/ c* B2 v: Kdl. range to stimulate phallic growth and secondary sexual
4 {) M& j0 `# c, `( A6 N% g2 jchanges. Therefore, after skeletal maturation parenteral tes-8 j; d. a4 ~: ~% ?( t5 n$ ?& G7 n+ s9 @
tosterone may be used to advantage. Before skeletal matura-( i# Q4 Z# H* Z
tion care must be taken to avoid maintaining levels of serum/ Y; N9 a. Y7 a/ ]  ?
testosterone more than 100 ng./dl. Low-dose gonadotropin
2 l# Y" A# q" A  X/ p: K$ u6 Zdepends upon intrinsic testicular activity and may require
+ w& f: O; F2 e* o) z4 w, c# Rprolonged administration for any response.
* e1 h! F# v2 C3 XAlternately, topical testosterone does not depend upon tes-
3 @. T. N  c, k  s8 g4 L; i8 Q; S  Rticular function and may provide a more constant level of
* ^& h" t1 k5 _2 j0 nREFERENCES
% o( @- P9 u! B& C1 p& F& A1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
5 y5 l! n5 t  g& s, v4 D$ L$ bR.: The local application of testosterone cream to the prepub-6 x: l; H* w/ z* m# ^
ertal phallus. J. Urol., 105: 905, 1971.
' ?5 D1 G# j- n, H2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone: {8 ^$ F3 z% b! C
treatment for micropenis during early childhood. J. Pediat.,# u: f  V; \+ ~4 X1 W
83: 247, 1973.; s- X* k0 f( G3 `  K
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
2 g5 p4 U& I* G" X! Pone therapy for penile growth. Urology, 6: 708, 1975.) S8 n& d- l$ f5 J3 n% O  r( B" r
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone* x5 N( ]+ w& W# I$ T
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ J  c4 T: Y% D; T. M
skin slices of man. J. Clin. Invest., 48: 371, 1969.
9 y- U4 z( N6 e$ T4 _; H# }" W" T5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth. K7 g+ Y+ C* o1 p) F
by topical application of androgens. J.A.M.A., 191: 521, 1965.
1 B. @3 J5 U2 w3 A0 u6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local. h* N$ q1 e( I3 N% K
androgenic effect of interstitial cell tumor of the testis. J.  p% }. z7 M* r' s/ f$ [1 k
Urol., 104: 774, 1970.
+ C: x: m3 m' S0 ^* s$ o7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
! X9 K3 J6 {; M. mtion in the male genitalia from birth to maturity. J. Urol., 48:
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