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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND6 z0 L& s) n8 z3 _5 N; y
GONADOTROPIN
( @/ U! c, G+ y5 N& C) ERICHARD C. KLUGO* AND JOSEPH C. CERNY
- |2 a1 s5 O) ]! v& U4 R* qFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
: y4 q! E) E/ h  C; r8 ^* wABSTRACT* P# b! f  g) \  A
Five patients were treated with gonadotropin and topical testosterone for micropenis associated0 `% W9 b9 ~4 k1 X4 n: V
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-2 r& Y. E. _9 s! K! L& r- @
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone. z0 P. \2 W- L! k% x8 n
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent9 _& d& X% t9 V/ [0 \0 [5 ?
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent' d4 g, D8 C3 I4 }* F+ R, @
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average3 G1 n* O: j- J
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response6 h3 j6 U# D/ U/ O
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
% I/ Q$ c4 R* @4 j2 Mstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" @0 K) |$ ]* s- G
growth. The response appears to be greater in younger children, which is consistent with previ-
% \$ M$ q' g* P! v2 f) _% [  f* }ously published studies of age-related 5 reductase activity.
9 D" }; e; b/ y' uChildren with microphallus regardless of its etiology will% G# I! ?4 Y6 I% y% X9 A/ z
require augmentation or consideration for alteration of exter-  q: F9 L& e% ]; S" k  r' r
nal genitalia. In many instances urethroplasty for hypo-$ v3 b: X& x! `1 R
spadias is easier with previous stimulation of phallic growth.# r9 A. T2 `: @) v
The use of testosterone administered parenterally or topically- b. r% x! G- Y/ G" a
has produced effective phallic growth. 1- 3 The mechanism of. Y- s4 j0 v' j: B, m
response has been considered as local or systemic. With this8 T1 \6 ]" d% G6 ~9 o- Q! P
in mind we studied 5 children with microphallus for response
* f0 ?2 R$ J  k' S5 n% M2 Cto gonadotropin and to topical testosterone independently.
' f  T! o# o3 G4 P6 w/ [$ q# l; N$ fMATERIALS AND METHODS5 l" }9 c4 B* @( ^& N
Five 46 XY male subjects between 3 and 17 years old were
/ }) e* z7 `. O: `% i+ V6 Bevaluated for serum testosterone levels and hypothalamic
" P* [- q* c( {7 Z; [" f; b1 Wfunction. Of these 5 boys 2 were considered to have Kallmann's
  f( q: j. t2 F) b6 tsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-/ e+ w; x: U7 R0 I5 {7 J/ y1 U
lamic deficiency. After evaluation of response to luteinizing
+ @, ?5 ?3 j, P4 `! w' ehormone-releasing hormone these patients were treated with
6 q; S$ E7 w4 A$ c1,000 units of gonadotropin weekly for 3 weeks. Six weeks: v3 m  k% H3 q
after completion of gonadotropin therapy 10 per cent topical
) @3 ?3 r6 S+ R- w, atestosterone was applied to the phallus twice daily for 3 weeks.
  L! v' k7 ?8 K/ a; zSerum testosterone, luteinizing hormone and follicle-stimulat-' g% i# h: W* A- Q, x
ing hormone were monitored before, during and after comple-
# Q3 p2 f  T- b& Z* [tion of each phase of therapy. Penile stretch length was
4 S- Q0 M/ _/ T: A# z% [( z3 vobtained by measuring from the symphysis pubis to the tip of! K* E# j, c1 u- P2 q/ ^' b! Q
the glans. Penile circumferential (girth) measurements were
6 Q/ [: W: W  m' Y* I) Y, B' Q8 uobtained using an orthopedic digital measuring device (see
0 ]$ K3 a' v2 D9 jfigure).& \6 S* b5 d% l+ V2 E
RESULTS3 G: [% U7 y( {- T% t
Serum testosterone increased moderately to levels between' U0 S3 F. ^$ E& W* U
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-2 d3 O$ q$ v! R2 Z' n5 S
terone levels with topical testosterone remained near pre-
7 y( G4 g0 n( ?. s4 ^- Ytreatment levels (35 ng./dl.) or were elevated to similar levels
7 O  R$ W2 I0 P) ?developed after gonadotropin therapy (96 ng./dl.). Higher8 p# k2 w0 t$ U* u% C0 a4 {$ y
serum levels were noted in older patients (12 and 17 years old),
$ j1 y+ o/ m; h: B6 N/ vwhile lower levels persisted in younger patients (4, 8, and 101 c+ V2 ]+ b5 a' ]
years old) (see table). Despite absence of profound alterations% W+ [* N8 Y( m  j% ^4 d
of serum testosterone the topical therapy provided a greater
. y7 z2 C; m7 CAccepted for publication July 1, 1977. ·
! b! z7 m6 V. E) X' X. U: `4 _& f5 uRead at annual meeting of American Urological Association,- h* {* e5 W1 h# [
Chicago, Illinois, April 24-28, 1977.% d. n) W$ ]0 k# S; C) X. o
* Requests for reprints: Division of Urology, Henry Ford Hospital,3 R  I' v8 P! g% I
2799 W. Grand Blvd., Detroit, Michigan 48202.4 Z5 m0 |4 z- f/ j
improvement in phallic growth compared to gonadotropin.
3 g  Q: P1 i4 ~" d0 L, \' Q0 EAverage phallic growth with gonadotropin was 14.3 per cent( c( x7 a  [% p: N
increase in length and 5.0 per cent increase of girth. Topical- p& o% W; A9 V
testosterone produced a 60.0 per cent increase of phallic length
- Q: A) f! a- ~2 J" z+ gand 52.9 per cent increase of girth (circumference). The
9 p3 V2 \5 C! J- j2 Eresponse to topical testosterone was greatest in children be-- C. K( u1 O) _6 h7 I' l
tween 4 and 8 years old, with a gradual decrease to age 17
1 T% B( `0 r- h; kyears (see table).
5 N1 f$ @# U9 n: o* }* \DISCUSSION
* T4 N: l$ P$ X1 R3 `2 q" ITopical testosterone has been used effectively by other2 z5 S( C5 z4 Y% C9 F
clinicians but its mode of action remains controversial. Im-$ [+ J( t+ e6 U8 p- v, V
mergut and associates reported an excellent growth response
, W5 {4 d" k. g) Kto topical testosterone with low levels of serum testosterone,
+ J8 q# s4 s# v4 Q9 `# Xsuggesting a local effect.1 Others have obtained growth re-
* z- ]  [. `4 c0 C" g$ S  t+ nsponse with high. levels of serum testosterone after topical3 f, d% `. ]' G) ^/ p
administration, suggesting a systemic response. 3 The use of8 S) b* W9 b- j' r# z
gonadotropin to obtain levels of serum testosterone compara-* ^. e. L2 x$ |3 _# s: D7 K+ Q' {  d
ble to levels obtained with topical testosterone would seem to  F) F) Y2 h/ E9 r1 f* ^8 Z
provide a means to compare the relative effectiveness of
, u9 R0 Q$ e2 {) Otopical testosterone to systemic testosterone effect. It cer-0 L! B0 x4 s- M3 r; X
tainly has been established that gonadotropin as well as par-5 t7 N4 s# J2 \9 g5 {0 ?9 e' A7 Q
enteral testosterone administration will produce genital
6 P; {4 o- E: x9 [8 o7 C& _8 w2 u1 kgrowth. Our report shows that the growth of the phallus was$ {# W% [) m4 Q, G2 @) C
significantly greater with topical applications than with go-
& M) w) Z3 Q" O( |7 b6 }nadotropin, particularly in children less than 10 years old.
8 e) q' R+ t- n7 W! bThe levels of serum testosterone remained similar or lower
" J$ a9 y0 @. }. p# I2 ethan with gonadotropin during therapy, suggesting that topi-9 _0 ?& S" ], U  b
cal application produces genital growth by its local effect as
+ ~' y3 J! y, d* Twell as its systemic effect.( E' C" e* n9 i4 n; S$ L8 L
Review of our patients and their growth response related to
3 E) g4 _: @+ V  A% g) p3 q5 zage shows a greater growth response at an earlier age. This is4 x8 c5 y8 A! L! e
consistent with the findings of Wilson and Walker, who
  J" ~; v# N. x3 z) O7 W& ~' {# wreported an increased conversion of testosterone to dihydrotes-  `0 u  @) Y: ]
tosterone in the foreskin of neonates and infants.4 This activ-0 J  @' V7 y) q
ity gradually decreases with age until puberty when it ap-
5 f8 h1 l6 @9 B( c6 Cproaches the same level of activity as peripheral skin. It may# t) [$ ], {1 M. u9 c, i' [/ h  ?1 U
well be that absorption of testosterone is less when applied at* d* J' `( B4 Y6 f
an earlier age as suggested by lower serum levels in children/ w8 R) ]! P* U& o, w
less than 10 years old. This fact may be explained by the
7 e. @1 b- W  F/ X% d7 W  c: S; {greater ability of phallic skin to convert testosterone to dihy-+ O: R6 X5 p5 [: X+ {
drotestosterone at this age. Conversely, serum levels in older
# ?. D1 J8 w, j& }patients were higher, possibly because of decreased local: A  V9 Y, _9 j3 v" F
667
& x5 _- y8 n0 k668 KLUGO AND CERNY
/ A; x+ P" }2 ePt. Age( Q+ q1 }5 c, N, M+ |# T2 W
(yrs.)/ v, _) i& B! f, R3 R5 u9 H
Serum Testosterone Phallus (cm.) Change Length
7 t3 @8 f. \9 B0 Q9 U(ng./dl.) Girth x Length (%)
3 o4 e4 h! S7 l- X) \4! k- ?/ P3 _. F. J4 J* t
8
. _/ \9 H2 m+ i+ j9 _10$ ]3 q# Z0 A0 s, s8 t: O! Y9 @
12
, D5 l: d3 m2 r: Y' F& \8 ~17
: p& W$ n2 i# Y9 [/ ^2 S# f2 b1 jGonadotropin1 {/ L7 W4 e% n' ?0 b3 r2 t
71.6 2.0 X 3 16.6
. N  E1 I; a1 `$ @' p  M: y4 Q50.4 4.0 X 5.0 20.0
- i& z3 G' g: o6 ?1 {; f1 u22.0 4.5 X 4.0 25.09 c& H2 Z- o  Q* p" a1 D
84.6 4.0 X 4.5 11.1. G" T/ O  t( q$ m. `
85.9 4.5 X 5.5 9.07 H  u$ j& q3 l3 P# |, p4 ^" u
Av. 14.3  S9 a( k1 W1 P4 c5 e- c8 e
46 y7 v# f: {( n& m0 Y
88 B- {) ?8 w& x
10
8 S% S6 f# S. M% J122 B$ C- `! E& E# {1 ]7 o$ k
17' v1 V8 X( r' @8 g& g8 E  r
Topical testosterone+ u5 Q2 i+ N: r1 O4 m- v( |: C* b$ m
34.6 4.5 X 6.5 85' P& ?. ?3 b2 `6 s0 R
38.8 6.0 X 8.5 70
/ }; q* Y7 h: Y7 X9 @( v40.0 6.0 X 6.5 62.5
( d: i+ N$ v8 |+ C7 K% P93.6 6.0 X 7.0 55.56 ?! x5 J" j, r: N2 L6 F
95.0 6.5 X 7.0 27.29 z6 s3 i8 `+ h- u: r. Q7 V
Av. 60.02 n+ f, X2 e% _! z( ^
available testosterone. Again, emphasis should be placed on( q( q; V0 S! Z1 d
early therapy when lower levels of testosterone appear to
. L1 S) |0 h3 w2 b+ lprovide the best responses. The earlier therapy is instituted! V. B* D( _7 p4 e7 |" L' {2 y
the more likely there will be an excellent response with low; X( y( l5 {* V) }7 X$ |4 J
serum levels. Response occurs throughout adolescence as# j; m6 \6 t5 m6 G0 @+ R
noted in nomograms of phallic growth. 7 The actual response0 i6 M7 k2 B6 u$ \. [
to a given serum level of testosterone is much greater at birth
9 {% ?+ ?2 c3 \% {( T+ l" w& Q7 o& }  Rand gradually decreases as boys reach puberty. This is most$ p/ L; Q9 M! f- V2 Y9 A
likely related to the conversion of testosterone to dihydrotes-
0 k$ |! E! ~) s# }tosterone and correlates well with the studies of testosterone$ A: L+ y9 f8 @" `! \0 K+ ~
conversion in foreskin at various ages.4 `% u5 f6 U) e
The question arises regarding early treatment as to whether- S9 E0 w* |$ Q1 o: ~+ P
one might sacrifice ultimate potential growth as with acceler-
% w  `  n1 i" n& oated bone growth. The situation appears quite the reverse, i3 a6 C. d1 u0 L7 e
with phallic response. If the early growth period is not used3 G4 S  {: {& Q! U+ q' H) e
when 5a reductase activity is greatest then potential growth
& m% E/ ^5 k+ B4 H6 T9 y1 ?may be lost. We have not observed any regression of growth
2 x6 u6 m$ N$ {attained with topical or gonadotropin therapy. It may well
" E- ^) ?; |- zbe that some patients will show little or no response to any
7 G$ F3 p" s5 i6 K6 T9 [form of therapy. This would suggest a defect in the ability to
; o. R; x$ ^5 Z. V$ ^; |convert testosterone to dihydrotestosterone and indicate that
: y; ?+ D' z0 zphallic and peripheral skin, and subcutaneous tissue should
# y3 O# V& N& d# v* S( O( r3 \; hbe compared for 5a reductase activity.% I9 u7 q4 Z4 [: K! g- ]2 i
A, loop enlarges to measure penile girth in millimeters. B,+ U8 y! C2 P6 L* [% j
example of penile girth computed easily and accurately.
: d# Z7 [5 k0 l5 s4 W3 U, s& {conversion of testosterone to dihydrotestosterone. It is in this# {9 {* D1 A" f, ]
older group that others have noted high levels of serum
( F: M! b$ W: ftestosterone with topical application. It would also appear1 p: n" R! T# l& w
that phallic response during puberty is related directly to the
( B/ F" e+ H( n4 K8 P2 Rserum testosterone level. There also is other evidence of local8 D4 s2 j! g- I4 r; A# u9 b
response to testosterone with hair growth and with spermato-! C3 n+ k4 [. y4 ~% B  y
genesis. 5• 6; |1 i# T: l$ T/ S& r# d
Administration of larger doses of gonadotropin or systemic& I; |. ~* M8 J, m9 N! i8 c, m
testosterone, as well as topical applications that produce
9 O  K  i* P+ s7 |& k3 S; Whigher levels of serum testosterone (150 to 900 ng./dl.), will+ w: ]$ `1 Z- k4 q
also produce phallic growth but risks accelerated skeletal
7 ]. _9 B# v: I0 Y! ]6 Ematuration even after stopping treatment. It would appear. ?5 j+ Y3 Q% J! k- a
that this may be avoided by topical applications of testosterone0 o4 U' u2 a& P/ P8 Y* ~
and monitoring of serum testosterone. Even with this control+ D+ N2 O9 Q% N1 @& R
the duration of our therapy did not exceed 3 weeks at any
3 e0 q) c* }, _7 k( I7 |" Itime. It is apparent that the prepuberal male subject may
1 T$ g8 c4 ?6 ^9 [* g9 O! N7 W0 Lsuffer accelerated bone growth with testosterone levels near
2 S+ }0 l& q) G# H200 ng./dl. When skeletal maturation is complete the level of
  Z/ o' w- P# C2 z, D, I9 bserum testosterone can be maintained in the 700 to 1,300 ng./
% O- [2 S' `7 o8 ?' F" Adl. range to stimulate phallic growth and secondary sexual
& y, v; o7 G) |+ [changes. Therefore, after skeletal maturation parenteral tes-! n, z2 w+ o, B
tosterone may be used to advantage. Before skeletal matura-$ ^( F3 r- R- ~0 r- D$ [  Q
tion care must be taken to avoid maintaining levels of serum& r  L3 s7 U# B4 v3 t6 R  [
testosterone more than 100 ng./dl. Low-dose gonadotropin1 f* m* A  y; [* w
depends upon intrinsic testicular activity and may require+ D- r, q- A) w) ~- }& R1 X2 O
prolonged administration for any response.
! w2 X  \) \- I- _2 f+ }1 \Alternately, topical testosterone does not depend upon tes-
$ g5 |' {+ E1 J( \ticular function and may provide a more constant level of
  \# w% O( I. C* `! vREFERENCES
8 E: P* @# B' p+ K6 D( Z1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,* P3 `' g- e0 J: ?. I' ]
R.: The local application of testosterone cream to the prepub-9 \$ Y5 W( o$ H: y6 u
ertal phallus. J. Urol., 105: 905, 1971.# I* `' S+ C, k
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) K! x2 C5 |# b6 `$ ?+ Jtreatment for micropenis during early childhood. J. Pediat.,1 ]: T; ^8 `4 a% v) v9 ?1 L
83: 247, 1973.9 j% W( _9 I. b' o' P1 O8 C
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" U, Q1 j. ~. j% c0 `' E8 w' aone therapy for penile growth. Urology, 6: 708, 1975.
8 u. a9 X$ h, @! |  n4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone2 f$ D$ ~+ v+ L8 }. i; y! a* o5 O/ H
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
! ]) x5 I! Q% j1 z0 Tskin slices of man. J. Clin. Invest., 48: 371, 1969.
9 ~0 @% F% J9 Q$ e( H5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% ?9 c) E; c" b/ v
by topical application of androgens. J.A.M.A., 191: 521, 1965.+ K( i" X' f* I+ [) n2 D
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
; N; v- n( A) l0 iandrogenic effect of interstitial cell tumor of the testis. J.
5 K8 P& r% x$ u4 B) B+ MUrol., 104: 774, 1970., h, w! N: C4 P/ {0 x
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
7 c3 u0 E/ h& ?6 \3 a5 X3 ]tion in the male genitalia from birth to maturity. J. Urol., 48:
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