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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND/ r/ W! P( t' v( L6 x4 P8 E
GONADOTROPIN+ G: u0 o7 P/ `
RICHARD C. KLUGO* AND JOSEPH C. CERNY
9 G. B" e$ H1 zFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan1 K+ A1 }' Q0 _3 _0 a4 a) {& @
ABSTRACT& u3 p" ]/ r9 V' R* e! Z$ ]
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
. V. q  p& o; n0 Y- y4 twith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ Q7 A# J* i4 c1 y) g- e/ o& etropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
  U; t, o3 I2 k+ Jcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
7 I) U) g, P( D6 W+ Ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent1 y5 X$ E4 w) i5 F/ P4 y" Q
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average8 {9 `! s1 Z; y! Z- ?8 |. x
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response* z( ]% O  v6 B+ F- Z
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This- G, l4 Y8 I7 K+ V& o7 U4 _
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% y, h2 X' A7 c+ K6 q& l# ~growth. The response appears to be greater in younger children, which is consistent with previ-3 m9 {' O2 L( S: q! j4 g
ously published studies of age-related 5 reductase activity.: R. r& b" _! h% z
Children with microphallus regardless of its etiology will! @% E2 e% P5 a/ ^
require augmentation or consideration for alteration of exter-6 r3 Z, o4 @1 h" ^: q5 O: P
nal genitalia. In many instances urethroplasty for hypo-
" ]# Y& h' A; g- m0 p6 B7 a0 ?5 |/ bspadias is easier with previous stimulation of phallic growth.
; E* `5 Y. i5 G' r3 tThe use of testosterone administered parenterally or topically
5 [5 `' h+ ]' f) ?) lhas produced effective phallic growth. 1- 3 The mechanism of
3 Q: f9 }! _2 F2 X! @; X" iresponse has been considered as local or systemic. With this
1 }9 d, J; p( d, Yin mind we studied 5 children with microphallus for response3 u! I  I' {% Y; o- }
to gonadotropin and to topical testosterone independently.
, V4 k' ?0 B* {2 ^5 D. DMATERIALS AND METHODS8 m* m5 g& O8 f( k9 t$ Y' W$ b
Five 46 XY male subjects between 3 and 17 years old were
3 T0 P/ r( t% M8 [  f' R2 revaluated for serum testosterone levels and hypothalamic1 S* l6 d* u5 j9 G% a7 l
function. Of these 5 boys 2 were considered to have Kallmann's
8 v5 u' T# @1 Q9 i% ~$ }: rsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
3 h' P1 z& A* ~( C; M( vlamic deficiency. After evaluation of response to luteinizing$ ~& T% R- s: Q2 d3 P
hormone-releasing hormone these patients were treated with
8 _7 C' B9 E1 A1,000 units of gonadotropin weekly for 3 weeks. Six weeks& @3 ?+ _$ J0 r
after completion of gonadotropin therapy 10 per cent topical
8 K6 \3 F9 C- |' V" g3 ttestosterone was applied to the phallus twice daily for 3 weeks.
5 x4 c) w" Z3 r- ?Serum testosterone, luteinizing hormone and follicle-stimulat-
3 n# ]0 l8 R, R0 cing hormone were monitored before, during and after comple-
8 X! m" c4 W& a7 v8 _2 ttion of each phase of therapy. Penile stretch length was
' J& d0 c" T  `" s5 ?# s7 Iobtained by measuring from the symphysis pubis to the tip of
9 s. N: j: b+ M# ?. ?' tthe glans. Penile circumferential (girth) measurements were; ?: U6 g# e6 Z  k9 {
obtained using an orthopedic digital measuring device (see
5 r& ^2 _; Z6 O. H, d- m; c4 Ufigure).
4 G" P1 h5 d7 x& S1 eRESULTS5 x9 Y- X& r3 w2 @3 @) @, D9 Q6 M
Serum testosterone increased moderately to levels between! I$ y. ~$ _, _/ l" ~3 P1 V3 L4 \* r& n
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-! v+ n- W* D; o# ]( X$ {) a
terone levels with topical testosterone remained near pre-0 C( X3 t% N# N6 j
treatment levels (35 ng./dl.) or were elevated to similar levels
/ r$ ?' m3 t2 j3 a7 s6 Gdeveloped after gonadotropin therapy (96 ng./dl.). Higher
/ X( b) @% E  o4 _serum levels were noted in older patients (12 and 17 years old),
  y8 y/ c7 ?5 N! {1 f, [) ~  S3 d' owhile lower levels persisted in younger patients (4, 8, and 10
% D! G/ o, ]6 e" dyears old) (see table). Despite absence of profound alterations" @4 j0 j+ L! f5 l, F8 F( o- |
of serum testosterone the topical therapy provided a greater
  h- w- i' C0 h, l9 v9 z7 OAccepted for publication July 1, 1977. ·
$ w: [+ _' c2 IRead at annual meeting of American Urological Association,- V9 a# X. m. S8 w: ^
Chicago, Illinois, April 24-28, 1977.  j: z, _- n) w+ o8 d
* Requests for reprints: Division of Urology, Henry Ford Hospital,
/ X; `) I2 Y! k+ T. x& R2799 W. Grand Blvd., Detroit, Michigan 48202.
' A! w5 }/ D( Y  O% Dimprovement in phallic growth compared to gonadotropin.
  h& m! d9 ]" ]Average phallic growth with gonadotropin was 14.3 per cent6 l8 I+ l9 h; U
increase in length and 5.0 per cent increase of girth. Topical
" v: K. f6 f5 e7 r2 t" b9 H3 ltestosterone produced a 60.0 per cent increase of phallic length
: l( v3 p8 a) Y8 O6 v5 c3 mand 52.9 per cent increase of girth (circumference). The
6 R4 O9 G% {) N. m/ l' Q$ W2 a3 tresponse to topical testosterone was greatest in children be-; t+ D! }. y9 ?
tween 4 and 8 years old, with a gradual decrease to age 17" A9 X$ f) m! \1 t, d7 i9 O
years (see table).+ ]" X% N# y, A# H" [7 V
DISCUSSION
3 T, j2 X6 l9 C9 q6 O3 s/ T5 M6 CTopical testosterone has been used effectively by other4 x( b6 Y/ l# `$ j! H
clinicians but its mode of action remains controversial. Im-
  n! O8 S4 U3 hmergut and associates reported an excellent growth response. G) t' v9 X$ z5 F4 v
to topical testosterone with low levels of serum testosterone,
9 {$ A, w3 g" f8 ]; b+ Bsuggesting a local effect.1 Others have obtained growth re-. |* h* e6 [$ f( `! Q: |9 k0 @" M
sponse with high. levels of serum testosterone after topical
; ~& I! d/ T8 F1 Z7 c' ?0 c! eadministration, suggesting a systemic response. 3 The use of( p; t% o5 T4 F! U% o
gonadotropin to obtain levels of serum testosterone compara-( E% p5 s$ v' ^- ]* @: b
ble to levels obtained with topical testosterone would seem to
" }3 x% ?, Y! K! J7 dprovide a means to compare the relative effectiveness of7 p/ I* H% v0 C
topical testosterone to systemic testosterone effect. It cer-
# i0 v' k7 |  W' i& ~tainly has been established that gonadotropin as well as par-; B$ A* f4 V& ]  q
enteral testosterone administration will produce genital
6 y3 Y4 [# ?! x6 u5 v% b  vgrowth. Our report shows that the growth of the phallus was
. r3 {* O+ d6 Psignificantly greater with topical applications than with go-! t- b! w& I6 \* J8 J* U
nadotropin, particularly in children less than 10 years old.# r) P4 _. Q% V2 k& n; H
The levels of serum testosterone remained similar or lower) y8 t  G# }& ^8 n- a
than with gonadotropin during therapy, suggesting that topi-) @- D3 u. z" ]2 G% l: j( ^: F
cal application produces genital growth by its local effect as5 L0 x2 C# X- q$ B* L2 h
well as its systemic effect." X7 N* m  k) a2 E
Review of our patients and their growth response related to
% X# C; C. ^' Z/ Rage shows a greater growth response at an earlier age. This is
4 T" A( n$ v, u  c/ Pconsistent with the findings of Wilson and Walker, who
: O1 {% z9 y' E" n0 {  T; v) greported an increased conversion of testosterone to dihydrotes-
5 ]2 }$ ~& C  q3 Rtosterone in the foreskin of neonates and infants.4 This activ-( i6 `9 s' }3 X0 a& B
ity gradually decreases with age until puberty when it ap-
' _( P' N; e" j6 j) v+ Iproaches the same level of activity as peripheral skin. It may
1 `1 {' \' n, e* C; u7 q6 ^/ @7 Rwell be that absorption of testosterone is less when applied at
1 w  {! z( J9 O: M4 a! t5 W+ }an earlier age as suggested by lower serum levels in children4 H( h$ `* z( Q
less than 10 years old. This fact may be explained by the, P" S4 x* A2 B
greater ability of phallic skin to convert testosterone to dihy-
+ ?- Y' r; z$ @' p' B) n5 Ydrotestosterone at this age. Conversely, serum levels in older, c; q9 H) J3 ^# O2 }% m
patients were higher, possibly because of decreased local# [3 B8 g9 m! s8 L! K0 N( e9 t! m. ?9 y
6677 v8 S7 m+ c; [
668 KLUGO AND CERNY) ?( U9 g  z; z1 V' B0 a2 I  \: I4 I/ C
Pt. Age6 M6 V5 [) V* k! N1 _
(yrs.)
9 c5 H( [+ O0 D$ I( ^% B# xSerum Testosterone Phallus (cm.) Change Length4 A& j( V- N$ g) l% X0 D' k6 G
(ng./dl.) Girth x Length (%); K$ Z4 H/ @+ ]7 j/ k" {
4) C- j# o: T9 Z2 a* Z
85 k- C+ r# x" w/ T3 T
10
9 m1 ?9 `, M0 V7 s* M( j4 ?- d12
0 I+ r( P4 M$ q17
9 Y, U5 ~9 q. l+ VGonadotropin/ Z  W8 u' c1 D" w
71.6 2.0 X 3 16.6
: _! c$ W; r1 \3 o( s& l50.4 4.0 X 5.0 20.0: E0 |( Q/ ?9 t
22.0 4.5 X 4.0 25.0
$ S4 ~7 J9 F7 |, h% Y  G7 j$ G84.6 4.0 X 4.5 11.1
, j7 S1 H6 \7 p9 ]8 O4 ~& n9 e85.9 4.5 X 5.5 9.0
4 M' W- F  F+ Y5 L& b' D6 ?5 [" }0 h/ G' XAv. 14.3% N$ }  ?, N  k5 b
4( u9 [$ f. F$ f/ I, c  |
8
7 ~1 u( ^/ F% c. n0 ^10
3 ~+ J  p2 r  l8 ]! Y3 g9 r1 I12, ~1 L! d2 l; f: _# X- P( ?, M. g
179 y1 A. S8 V: z: M# u6 b
Topical testosterone: S6 k& t6 ~" a' f* I5 F
34.6 4.5 X 6.5 85
( ~6 D9 J7 w, t# f( q4 Y% D  ~; v38.8 6.0 X 8.5 70
& @3 I1 a" h! b3 Y40.0 6.0 X 6.5 62.50 z/ Q" z: m6 N6 R0 |3 c: S
93.6 6.0 X 7.0 55.5/ p: a& S" H# D; t: o
95.0 6.5 X 7.0 27.2+ w' t8 T" J/ K" G1 F
Av. 60.09 q% E4 u4 B$ f3 L' l
available testosterone. Again, emphasis should be placed on
, s, e/ _( }% z+ W0 Bearly therapy when lower levels of testosterone appear to/ \% r$ |3 f3 I- r2 z
provide the best responses. The earlier therapy is instituted0 `8 p, W. t. R- |% o
the more likely there will be an excellent response with low
$ y  L7 E: ?+ B- P  M6 X* b& ^/ }! Sserum levels. Response occurs throughout adolescence as
6 G6 |; }' v- l4 u4 Anoted in nomograms of phallic growth. 7 The actual response
& C$ F8 J& k- S% y7 u, v) W3 n5 }5 Mto a given serum level of testosterone is much greater at birth
: O/ q0 i6 e" Jand gradually decreases as boys reach puberty. This is most
7 N  _7 R* b% A) V0 w! Y, T$ Mlikely related to the conversion of testosterone to dihydrotes-
; _4 l4 K- g2 T' z8 stosterone and correlates well with the studies of testosterone; b! M3 T; h% ?( v# b2 d
conversion in foreskin at various ages.
) y! I; w" J7 l* ~7 yThe question arises regarding early treatment as to whether: Y! z  E' {/ q  b
one might sacrifice ultimate potential growth as with acceler-
" b/ ?7 n. h' Z; L# g' v5 Eated bone growth. The situation appears quite the reverse
. b- o0 W1 d; I1 g+ w3 R$ Qwith phallic response. If the early growth period is not used. ]! o. s. X' R
when 5a reductase activity is greatest then potential growth. i' R- ?& ]! W9 E% N* |
may be lost. We have not observed any regression of growth7 m; T  @6 L& v/ j8 C
attained with topical or gonadotropin therapy. It may well. N/ i- L7 `& O3 V8 a
be that some patients will show little or no response to any9 J3 {% {$ ~  K. C8 P% z! L9 W
form of therapy. This would suggest a defect in the ability to
3 r2 C1 x" S  M$ N4 [" F) Hconvert testosterone to dihydrotestosterone and indicate that( j' y5 w; X3 y3 z* K+ V! l5 w: @8 o2 j
phallic and peripheral skin, and subcutaneous tissue should
; T" c. b4 Z# ^' |7 {- L3 bbe compared for 5a reductase activity.' t9 d( F' i% f
A, loop enlarges to measure penile girth in millimeters. B,
5 ^% s2 B( x% m& z. n1 v) Bexample of penile girth computed easily and accurately.1 p; ?; m; ^. B+ p1 [8 D! c
conversion of testosterone to dihydrotestosterone. It is in this$ v" V" `: M; Q/ v. ?: r7 p
older group that others have noted high levels of serum9 j; G+ b, S# Y6 K/ M
testosterone with topical application. It would also appear
( w6 {! ?4 p- e5 |. `' fthat phallic response during puberty is related directly to the
7 {0 \: [0 b- Tserum testosterone level. There also is other evidence of local
9 s3 n$ d5 ~$ c0 Eresponse to testosterone with hair growth and with spermato-
$ O3 v2 u2 P- M9 O" R5 p! Vgenesis. 5• 6
3 Y( N! r  c, d5 }! c1 w' V8 S3 K7 c/ KAdministration of larger doses of gonadotropin or systemic$ y# ]8 g: t  P: u
testosterone, as well as topical applications that produce6 q, \9 I0 k0 A) M
higher levels of serum testosterone (150 to 900 ng./dl.), will7 v  ]/ i5 f: w3 r" ]9 X
also produce phallic growth but risks accelerated skeletal' m4 b! J+ K' |; Y' ?: t( v& \4 ]
maturation even after stopping treatment. It would appear
6 S: j5 {5 L& Mthat this may be avoided by topical applications of testosterone& y. f5 q- X3 ~: |3 u
and monitoring of serum testosterone. Even with this control
) {/ \. {* e& mthe duration of our therapy did not exceed 3 weeks at any
) f# g% [2 p  T* M* q% }time. It is apparent that the prepuberal male subject may
1 j  U+ n+ `  vsuffer accelerated bone growth with testosterone levels near
( S! v6 |1 s8 W3 E200 ng./dl. When skeletal maturation is complete the level of! ?5 H8 I0 T" K' F, o
serum testosterone can be maintained in the 700 to 1,300 ng./
" o. _6 D' o) c$ x0 a2 Mdl. range to stimulate phallic growth and secondary sexual& n+ a; O4 o* ?$ t
changes. Therefore, after skeletal maturation parenteral tes-
1 u- a6 }8 S" V* ^5 T& [tosterone may be used to advantage. Before skeletal matura-
7 Y& ?* |/ m) [. u' \' ntion care must be taken to avoid maintaining levels of serum: ]# L3 \/ q& ^/ Z
testosterone more than 100 ng./dl. Low-dose gonadotropin0 k/ w5 @3 W* U* r
depends upon intrinsic testicular activity and may require5 b) \* f# e$ G  k
prolonged administration for any response.6 G: Z) C& j; O8 _( x) c( x) j  I
Alternately, topical testosterone does not depend upon tes-
9 Q$ e, ]( I. a" g0 E2 sticular function and may provide a more constant level of; a) x. |& d+ |+ L+ M' r
REFERENCES
1 b, Y7 d- f9 D# a! n- t- y1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
$ M. X0 h5 O2 ]R.: The local application of testosterone cream to the prepub-4 ^; @7 [0 Z7 I8 M8 y
ertal phallus. J. Urol., 105: 905, 1971.0 u, A9 U( X, m/ g+ w
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# c8 O6 q( [5 C( B. W
treatment for micropenis during early childhood. J. Pediat.,
# n+ z/ k+ L' V3 _3 f0 m8 b83: 247, 1973.& Q& G9 b4 b  ?; m+ T9 ?5 G: Q
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
/ g" O$ d, a! \  X$ Wone therapy for penile growth. Urology, 6: 708, 1975.
/ Z6 n7 B8 a2 @. D, f0 l3 C! O4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone; k( d& V3 t: P# \
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, s, w  C5 \6 k2 X( Q  jskin slices of man. J. Clin. Invest., 48: 371, 1969./ Z$ M2 L$ J3 z
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 [0 O$ k; w' T1 @. O. ^- ~3 K
by topical application of androgens. J.A.M.A., 191: 521, 1965.$ W6 F) i0 n* O# }
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
3 I" n5 R9 X& _9 Q$ v. n; y6 aandrogenic effect of interstitial cell tumor of the testis. J.
2 k, g6 D* m7 Z8 I# iUrol., 104: 774, 1970.8 f( N* U7 a9 p; ], k  }
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 h/ Q) u" j* x2 B+ I2 U( Q$ dtion in the male genitalia from birth to maturity. J. Urol., 48:
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