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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND+ j' [2 j, H, x$ R; ~. T
GONADOTROPIN3 W) a" u# R2 Y0 E
RICHARD C. KLUGO* AND JOSEPH C. CERNY4 k3 j0 \* Z: R0 o+ h% e' W. G* `
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan. L5 x$ ~# t* v" _( A! x
ABSTRACT; k' D+ l: \, J9 Q
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
3 }+ `: g9 Y2 `$ p3 X, C* b1 `with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
- M5 L: m7 x- A6 _" i6 ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone7 N! D5 ^- f5 X8 c" O
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
3 A' z5 J7 M# i5 m& K$ afor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
$ ?7 z6 E9 ~9 S: ]& Nincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
$ g4 m1 {* j2 h+ D0 k8 w. Q* Lincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
9 i; D: L: h6 X; g! t6 X& ioccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
" i, F6 L6 c- i* x7 Ystudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile& @* ]* t2 M# o6 @0 T6 A" w. O
growth. The response appears to be greater in younger children, which is consistent with previ-! m1 _; l2 U, v
ously published studies of age-related 5 reductase activity.3 N, k" L5 U+ j2 O2 b
Children with microphallus regardless of its etiology will1 P  [( L, e# P9 g( ~4 t1 {- F
require augmentation or consideration for alteration of exter-
3 K/ _4 C& ^* T$ x6 ?. l$ {nal genitalia. In many instances urethroplasty for hypo-+ A% s+ m4 O9 M7 Y4 W. k
spadias is easier with previous stimulation of phallic growth.
- ]7 Z: J: M6 `8 `# rThe use of testosterone administered parenterally or topically
/ o' ?, K, \2 Y5 u9 Hhas produced effective phallic growth. 1- 3 The mechanism of
) G( Q' U# _8 aresponse has been considered as local or systemic. With this( {8 M3 @/ R- @8 m: }" I: f
in mind we studied 5 children with microphallus for response, f0 h9 x& C) Z1 r2 S  Z& p4 v
to gonadotropin and to topical testosterone independently.
9 `' z( y$ g  \7 l6 u1 YMATERIALS AND METHODS
$ b$ d3 c$ C& J" C' i* K6 h  ZFive 46 XY male subjects between 3 and 17 years old were& F: L1 }2 e4 Y4 B( h- w
evaluated for serum testosterone levels and hypothalamic6 l7 a5 ], ?' j/ i
function. Of these 5 boys 2 were considered to have Kallmann's
, r! R  M; m  T6 ~0 i' s3 ?syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
3 W7 Z; j8 B2 Z% w1 I% y! Ilamic deficiency. After evaluation of response to luteinizing
/ K& i+ k, x, C$ S, }4 E4 Lhormone-releasing hormone these patients were treated with6 P/ i/ P" I2 R  z# V
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
6 Q" {7 ?6 Q5 y& g" G! F3 H" |after completion of gonadotropin therapy 10 per cent topical* F3 L3 {' _+ f$ @0 u
testosterone was applied to the phallus twice daily for 3 weeks.
0 N$ B) }7 o( X' V) ASerum testosterone, luteinizing hormone and follicle-stimulat-
' B3 h; V/ ]! ^( F/ T4 cing hormone were monitored before, during and after comple-
. a+ O* E* Z8 ~. Qtion of each phase of therapy. Penile stretch length was' Z" I4 [) _  o' L
obtained by measuring from the symphysis pubis to the tip of
" T" m/ L2 ^2 mthe glans. Penile circumferential (girth) measurements were
2 R' I$ U+ A( K% @' V; wobtained using an orthopedic digital measuring device (see
3 @2 ]' {5 Y3 m6 U( D# R1 N1 tfigure).  S  ~/ y. \) n. H3 b
RESULTS
( k4 x2 ^0 p5 M* W; ?. \$ m3 ]: TSerum testosterone increased moderately to levels between
; D" G. C4 g1 G7 V4 U, h50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-/ T' k/ O) q0 d  e7 o8 w4 B
terone levels with topical testosterone remained near pre-" }' j% c3 `7 a/ _. L5 n$ @9 J9 r
treatment levels (35 ng./dl.) or were elevated to similar levels
& P. `- s$ O2 O5 M. W& udeveloped after gonadotropin therapy (96 ng./dl.). Higher1 n  U" b5 I2 |; A
serum levels were noted in older patients (12 and 17 years old),
! X; s; _+ |" G) w" K) d; _while lower levels persisted in younger patients (4, 8, and 10
: I& E5 m7 M! ?years old) (see table). Despite absence of profound alterations
5 A: N5 \$ F. u0 W6 d9 K! Rof serum testosterone the topical therapy provided a greater% U* N# f1 b. f) O; G6 o/ b
Accepted for publication July 1, 1977. ·; Z0 @9 v! a( M
Read at annual meeting of American Urological Association,0 I8 h4 q; m) t- b1 M0 i2 A' X
Chicago, Illinois, April 24-28, 1977.7 V3 v  h- W" x2 S3 Z2 a* H
* Requests for reprints: Division of Urology, Henry Ford Hospital,
0 n8 P& F& `9 d  O: M* C2799 W. Grand Blvd., Detroit, Michigan 48202.
* o2 ]+ _2 q" e6 simprovement in phallic growth compared to gonadotropin.! F) B" U' a8 U: t
Average phallic growth with gonadotropin was 14.3 per cent
" B( V( @* L% c" Zincrease in length and 5.0 per cent increase of girth. Topical
; k2 q* c; v2 R* H% ?8 C. C& B5 Ltestosterone produced a 60.0 per cent increase of phallic length
5 G8 s6 C2 f9 a' p" m! Cand 52.9 per cent increase of girth (circumference). The1 W1 ^, V' Q2 m3 V8 D, v1 X
response to topical testosterone was greatest in children be-# v  G# J2 H" A, b: s' x$ ]2 ~
tween 4 and 8 years old, with a gradual decrease to age 172 x: s3 \8 ^1 C& ]+ {
years (see table).
  F; m7 ^% h. h$ {) @) ]DISCUSSION
) z7 Z  C/ z* m% V4 X( {! O4 \Topical testosterone has been used effectively by other
) `) P4 t5 D: m8 nclinicians but its mode of action remains controversial. Im-
2 T1 k1 C- M+ n- Pmergut and associates reported an excellent growth response1 e9 S" b1 s+ I9 e
to topical testosterone with low levels of serum testosterone,
( ]: i- Y7 P2 g; a6 [" s3 Lsuggesting a local effect.1 Others have obtained growth re-# |9 P$ |" s' l! Z7 `  [
sponse with high. levels of serum testosterone after topical: q1 s4 K! y9 T& _0 a! \" A
administration, suggesting a systemic response. 3 The use of$ u+ T0 R3 c$ l; `. u. B) t  T7 ^4 ~
gonadotropin to obtain levels of serum testosterone compara-
: b4 w- n* j8 @* q1 F3 {ble to levels obtained with topical testosterone would seem to& O( {& w2 T3 N0 L3 R
provide a means to compare the relative effectiveness of% r* ?6 }- |: J4 ?
topical testosterone to systemic testosterone effect. It cer-
: @. w: x" m' {  @! Q% C# i8 ktainly has been established that gonadotropin as well as par-
& B) _* {# k2 e/ s5 [enteral testosterone administration will produce genital
' l6 {# q; }& z! Tgrowth. Our report shows that the growth of the phallus was
% [6 N0 Z& ^* b0 B$ N0 i$ Csignificantly greater with topical applications than with go-
6 B6 N* ~. C) dnadotropin, particularly in children less than 10 years old.
4 e" n# ]/ B+ F& f/ CThe levels of serum testosterone remained similar or lower1 H0 m- Z( m1 t. [! x2 y- x
than with gonadotropin during therapy, suggesting that topi-0 K* w& W1 a' X! d! C
cal application produces genital growth by its local effect as
# }9 P2 W4 W3 k+ P* R+ m9 Swell as its systemic effect.8 P% W; ]7 j3 f$ `
Review of our patients and their growth response related to: z& R. f9 U' R) J. R9 g8 X  x
age shows a greater growth response at an earlier age. This is5 D0 [/ r1 f1 v1 T! L( r  F" I
consistent with the findings of Wilson and Walker, who3 Z) e( R  s" I) d9 a; o
reported an increased conversion of testosterone to dihydrotes-- }# L4 K9 }% m1 q! r7 B
tosterone in the foreskin of neonates and infants.4 This activ-8 `' d4 ?5 R' j" C/ k
ity gradually decreases with age until puberty when it ap-
+ ~3 n+ ^! \# p. H' }( X: w& f( Yproaches the same level of activity as peripheral skin. It may- G6 ]+ R% E! E1 x' j) Z0 y
well be that absorption of testosterone is less when applied at9 b8 f& F: X) Y  v. A0 {
an earlier age as suggested by lower serum levels in children
1 R2 J  c$ J) |( h% c7 ^% }less than 10 years old. This fact may be explained by the
$ z) S/ a+ r0 C2 R$ I% Rgreater ability of phallic skin to convert testosterone to dihy-! |, f" I; p# m
drotestosterone at this age. Conversely, serum levels in older$ j6 v; v8 N3 [; }. v* Q
patients were higher, possibly because of decreased local
5 ?% I4 @4 G. S/ M* M! a( r- }667' B" {0 p: i6 D6 H
668 KLUGO AND CERNY
- {0 t! Q+ {# x. YPt. Age9 ^" O' e- J& H# V# y: e# P
(yrs.)
, j2 M  r: s3 o7 e$ `$ r# B1 e6 r9 NSerum Testosterone Phallus (cm.) Change Length) L0 I1 t* i7 k+ c
(ng./dl.) Girth x Length (%)
( U5 C( e6 O2 c9 S  Z: K$ }46 Y3 @0 M# k6 r
8% y6 a* u( _: V( a4 V. {
10
% J" G4 C& M5 P" f+ e. a1 D12
0 f( M- \( I) c4 o175 w1 m* ^; w' M/ k3 F* R6 z
Gonadotropin% M& K/ C. A- a0 g* ^
71.6 2.0 X 3 16.6: z8 g, p; W. E
50.4 4.0 X 5.0 20.0" c0 j3 a/ M) X0 U7 z$ f3 A
22.0 4.5 X 4.0 25.0
7 f* R; ~% B" X- {6 ~5 n84.6 4.0 X 4.5 11.1
2 }8 w( W  \& k" H+ O2 N% m5 i+ K85.9 4.5 X 5.5 9.02 X) b# _! ?- v9 C9 O8 b
Av. 14.3# `: ^' Z% v) e5 r
4
& Z1 I) {' t! Y3 M9 k- d* o+ g! f% G8
! h/ ?1 C+ l3 V& [; Z% r10, ~/ h; [/ B8 I2 c2 d
12
; i% V) e2 z! {/ V" U( m17
1 W. _$ q+ W; u6 CTopical testosterone* O/ m! K$ p2 q8 Z( L3 i: }
34.6 4.5 X 6.5 85! y& ~% r& P* }/ d# A7 i" q
38.8 6.0 X 8.5 70
8 d* B7 X) V4 K7 @5 N" h40.0 6.0 X 6.5 62.5
6 ?0 x  n' j% o$ ?5 u93.6 6.0 X 7.0 55.5& i% X8 y9 w- Y" \- ?+ i
95.0 6.5 X 7.0 27.22 _5 H6 @- R" t9 B( e, W1 p
Av. 60.0
0 V% c2 p6 O* p6 havailable testosterone. Again, emphasis should be placed on
) q. K' \0 ~3 w6 P+ |4 D' x9 \1 @early therapy when lower levels of testosterone appear to7 }! V# H' N( `0 v
provide the best responses. The earlier therapy is instituted3 N( k9 f# L- ?9 R0 j
the more likely there will be an excellent response with low
5 J  c' L% u+ r0 a9 w2 |serum levels. Response occurs throughout adolescence as- G9 c: P+ z$ W; E( m* B9 Z, D
noted in nomograms of phallic growth. 7 The actual response
( g1 o# p0 I) B! c2 Lto a given serum level of testosterone is much greater at birth# c; a  D$ u2 W$ o
and gradually decreases as boys reach puberty. This is most. d% I  C& w0 M
likely related to the conversion of testosterone to dihydrotes-6 e2 p  t8 p2 V& y$ P* c% |
tosterone and correlates well with the studies of testosterone3 Q  G) b* l6 f
conversion in foreskin at various ages.
* O& K9 p0 l# W+ D" uThe question arises regarding early treatment as to whether) a3 _# q2 s: ]& h6 u
one might sacrifice ultimate potential growth as with acceler-, W% q7 F, U! b
ated bone growth. The situation appears quite the reverse
; J/ a8 {  @* s5 f7 e$ O; Mwith phallic response. If the early growth period is not used
4 I- S: \; v# V  p0 uwhen 5a reductase activity is greatest then potential growth
4 s/ b( d! V& y" u- R4 J) pmay be lost. We have not observed any regression of growth8 Y2 d0 B% b6 a5 N% s# b
attained with topical or gonadotropin therapy. It may well
9 C' @5 ]2 U0 Q. G- a* ^be that some patients will show little or no response to any+ k6 [) m* c% w4 ^
form of therapy. This would suggest a defect in the ability to% u$ s- l( \& U8 L: T
convert testosterone to dihydrotestosterone and indicate that
- R% @- ]. h1 N. H( `# ]phallic and peripheral skin, and subcutaneous tissue should; c0 B1 O  B. V+ g" }/ p
be compared for 5a reductase activity.
8 a# V" Y1 s3 n: n; p. XA, loop enlarges to measure penile girth in millimeters. B,
5 S8 |* a! \( G. {example of penile girth computed easily and accurately.
- h+ J! n# i1 J: Q$ uconversion of testosterone to dihydrotestosterone. It is in this
" M6 x4 A4 D0 r7 b# G$ nolder group that others have noted high levels of serum
% T' l% a: f5 X* @! X* B4 ztestosterone with topical application. It would also appear
4 g' K) u- O; T6 rthat phallic response during puberty is related directly to the0 I- A5 J0 ~4 b4 ^$ P" v
serum testosterone level. There also is other evidence of local# g2 G& Z! H8 \# O) g0 I
response to testosterone with hair growth and with spermato-! W/ l( `( o& B& [" s) v
genesis. 5• 68 [4 f. o# E. {' _/ r
Administration of larger doses of gonadotropin or systemic6 \" ]4 C- u2 v$ y) m5 ?
testosterone, as well as topical applications that produce9 `2 l5 i3 T+ J, h, c# P" M, f9 m
higher levels of serum testosterone (150 to 900 ng./dl.), will
1 ]- g2 c( x9 L& j! malso produce phallic growth but risks accelerated skeletal
  L! r! H6 t0 n6 f1 |( Ematuration even after stopping treatment. It would appear
) r0 D* a; O5 Z: D4 A6 }that this may be avoided by topical applications of testosterone
  U5 L8 @6 \- u7 P0 Z& m0 Yand monitoring of serum testosterone. Even with this control( D. \7 ^# ?) H& e0 ~% C, a5 ^
the duration of our therapy did not exceed 3 weeks at any
% U# Q! l0 B' A1 ^! Qtime. It is apparent that the prepuberal male subject may: ~& h+ h- U8 h4 s/ E
suffer accelerated bone growth with testosterone levels near
- w8 }3 a' D  r+ T% D" B. k200 ng./dl. When skeletal maturation is complete the level of
! k# A' r$ Y3 J5 ~7 H# v  Fserum testosterone can be maintained in the 700 to 1,300 ng./5 X& N9 R; g  K
dl. range to stimulate phallic growth and secondary sexual- B- X( y8 S. D! @, T
changes. Therefore, after skeletal maturation parenteral tes-
9 r& v+ m/ H8 S8 w( {9 Wtosterone may be used to advantage. Before skeletal matura-5 I1 h1 c3 e* O  k' R6 _
tion care must be taken to avoid maintaining levels of serum3 M) c9 {( s  B! E4 W" x% h) X
testosterone more than 100 ng./dl. Low-dose gonadotropin
  C* k# D, G- H- v3 z6 qdepends upon intrinsic testicular activity and may require! D  }; N. z7 b& E+ d. I( ?" {
prolonged administration for any response.$ E; h; D! [' k$ }
Alternately, topical testosterone does not depend upon tes-' m; x! X1 y7 Q) c1 f
ticular function and may provide a more constant level of
) Z( x% e) D5 e' l5 c; p' aREFERENCES3 `* _4 q, n( y
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
+ }7 M& e* D4 N+ D2 y: n" V, CR.: The local application of testosterone cream to the prepub-
5 [8 h) d! g) nertal phallus. J. Urol., 105: 905, 1971.
: B) o0 H, ^* k- y0 @$ y2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone5 Q- u& S$ J) ~; B1 P
treatment for micropenis during early childhood. J. Pediat.,
$ `% q$ x( _! l! O. t83: 247, 1973.9 E: d+ a# Q) e
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 m7 t2 {( R& A; Xone therapy for penile growth. Urology, 6: 708, 1975.
* c* |, D) o) c. ]4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
& j: F# _* |5 h& h. m8 Kto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
& N. g+ p- o, f0 s6 r1 }/ u. _skin slices of man. J. Clin. Invest., 48: 371, 1969.4 J$ H" T- v* U' E  ^& A
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
3 ~, a5 v' }) s1 Z+ R* p3 V8 m6 g! Yby topical application of androgens. J.A.M.A., 191: 521, 1965.
# F4 w1 K' {. q. E' y7 d2 a6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ G' t( c5 k* q# l( ]/ ]1 k. M$ x
androgenic effect of interstitial cell tumor of the testis. J.
5 w( d0 r4 ~# H* a) d2 D' A) nUrol., 104: 774, 1970./ F% ~% G, T; g8 \" D6 X. P
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( N1 p! I( l' G3 J$ w  r$ a
tion in the male genitalia from birth to maturity. J. Urol., 48:
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