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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
  ^: h; \/ [9 U5 U5 n8 A6 ~0 U) NGONADOTROPIN* t$ e" U0 G  b  V4 o, q  ]3 K$ K* l
RICHARD C. KLUGO* AND JOSEPH C. CERNY% ]' A; f) n) t0 R( n3 D' `
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
- K0 }3 ?6 x6 H( [# Q7 U) H* yABSTRACT8 W0 X0 j5 n" z% _& G* T
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
: C$ |$ c! l. y7 |- V. Hwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-) q/ l1 m  T) v2 v4 J$ Z. {
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
3 w/ G* E% f# _  T4 [& K5 R+ w9 Hcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
) {2 R: m( |$ \/ R4 gfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
5 u. o7 g+ L$ `& kincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average' |/ f9 s. @  w1 d0 G7 D
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
9 N2 C8 q: W1 J! g, |occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This2 O- i6 f: w4 ]# u; G6 _5 L7 U) _
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
0 I& {/ T* ?. _7 q( T$ agrowth. The response appears to be greater in younger children, which is consistent with previ-
- s  W* W  K, pously published studies of age-related 5 reductase activity.
" l7 D* N0 L( d7 b  e0 UChildren with microphallus regardless of its etiology will- N$ }9 A. B1 N; J  u$ Z. l$ n( X; g8 W
require augmentation or consideration for alteration of exter-
2 k* f  s, i& `* u/ [3 Bnal genitalia. In many instances urethroplasty for hypo-
: `  x7 T0 G. [; V% l" L: tspadias is easier with previous stimulation of phallic growth.
2 A- q$ O! x* c  M7 xThe use of testosterone administered parenterally or topically
( F2 H9 {$ p5 }  L3 @( chas produced effective phallic growth. 1- 3 The mechanism of
) p/ j) X/ f7 U! c- V( @response has been considered as local or systemic. With this
- U& ~2 i/ S2 K1 h; a: _6 @: B. kin mind we studied 5 children with microphallus for response
. Q) f0 c8 `, c1 _* Y* \8 zto gonadotropin and to topical testosterone independently.
) t! ~9 F0 v2 t7 I% v) YMATERIALS AND METHODS2 X- S/ ?* X1 N
Five 46 XY male subjects between 3 and 17 years old were
# c% T" Q8 t" X" c) V/ ?  `evaluated for serum testosterone levels and hypothalamic
) |2 `- a! [% ^' F4 b1 q4 `function. Of these 5 boys 2 were considered to have Kallmann's
6 l. k' ?5 K, ?9 p( J, U! n- wsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-  o/ E6 }, L* _8 L
lamic deficiency. After evaluation of response to luteinizing
& J  d. H. d6 I# J5 f: n( Rhormone-releasing hormone these patients were treated with
2 ]% n  X! M3 V: Z1,000 units of gonadotropin weekly for 3 weeks. Six weeks
0 j( `# X2 y  o: wafter completion of gonadotropin therapy 10 per cent topical
2 H/ x5 A; t/ J/ ?testosterone was applied to the phallus twice daily for 3 weeks.2 k3 a- [1 ?/ c$ `6 o$ v  Y7 a: N
Serum testosterone, luteinizing hormone and follicle-stimulat-
( v2 a; D( Z( I4 _; fing hormone were monitored before, during and after comple-1 _9 N* C- o$ R; z
tion of each phase of therapy. Penile stretch length was
3 z0 j% L; Z- z7 ^obtained by measuring from the symphysis pubis to the tip of' t4 A) q# r1 }- P' M/ i
the glans. Penile circumferential (girth) measurements were
/ \# u1 L* ^% s+ c" x* [1 Wobtained using an orthopedic digital measuring device (see6 J) a# [% i1 }1 [
figure).
: A/ H- F7 b/ H& fRESULTS, \* Y/ [, x- g) J! W: z/ m" G
Serum testosterone increased moderately to levels between7 X# I7 m. Y2 q  I& u
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
4 r; w$ q8 U& Cterone levels with topical testosterone remained near pre-5 |  v7 w+ V1 q9 F. T7 |9 U- ?  Y4 M
treatment levels (35 ng./dl.) or were elevated to similar levels
% @- V" i" }4 Ideveloped after gonadotropin therapy (96 ng./dl.). Higher: o! o. J; I# E. D
serum levels were noted in older patients (12 and 17 years old),
3 F1 B3 k% J6 @while lower levels persisted in younger patients (4, 8, and 10
. Q  z  B$ P& ~: F  A% myears old) (see table). Despite absence of profound alterations4 i& h4 @! r+ S; G
of serum testosterone the topical therapy provided a greater1 Y* j6 Y+ V0 W/ g5 s
Accepted for publication July 1, 1977. ·
! U  R+ ~& {* F7 ^* xRead at annual meeting of American Urological Association,% x6 ~. Z; M$ w: g. H4 b  N8 K2 }
Chicago, Illinois, April 24-28, 1977.
7 n4 f" ]! {9 g* Requests for reprints: Division of Urology, Henry Ford Hospital,
- Y6 e  C2 l! U2 Q: w1 r8 C+ E2799 W. Grand Blvd., Detroit, Michigan 48202.+ W, m( z1 A' x( w4 p3 p
improvement in phallic growth compared to gonadotropin.9 `. q4 U1 F+ `6 G. a$ C
Average phallic growth with gonadotropin was 14.3 per cent* L, n% r- q& F8 T( O9 Z
increase in length and 5.0 per cent increase of girth. Topical
9 l) N% ?5 i& H2 Xtestosterone produced a 60.0 per cent increase of phallic length
  ?* X& J: R1 ^and 52.9 per cent increase of girth (circumference). The$ d: l+ W4 u6 I& }# Y4 |3 F
response to topical testosterone was greatest in children be-# M  O- B; X! H% h& \. C2 s
tween 4 and 8 years old, with a gradual decrease to age 17/ y4 V  J- L& Z6 P2 e" s, {" Q/ f
years (see table).& U6 L" W9 V  j" V8 O1 P5 J# D3 E
DISCUSSION! i+ h" n* ~5 J, ~5 x" w! i
Topical testosterone has been used effectively by other
1 [4 j1 I' @( D) W* b: A3 f% \0 kclinicians but its mode of action remains controversial. Im-
( t, o- Y; Y$ O8 Xmergut and associates reported an excellent growth response
" U8 K- }3 E1 q) N' ^) U. b2 _% hto topical testosterone with low levels of serum testosterone,
! |4 u8 J( L* rsuggesting a local effect.1 Others have obtained growth re-' R. D9 t, g! r" e$ s5 ^3 {
sponse with high. levels of serum testosterone after topical4 Q+ g; Q, m3 H
administration, suggesting a systemic response. 3 The use of
; i( {) |& e" f* B  l9 Q; l/ igonadotropin to obtain levels of serum testosterone compara-
  G6 m! S& q  k: ]  [ble to levels obtained with topical testosterone would seem to& @3 a: h% V& x  E6 j( h& J1 l, n
provide a means to compare the relative effectiveness of$ ~0 d- S4 Z# t% g" |. r
topical testosterone to systemic testosterone effect. It cer-% d0 B2 Q0 I- ?
tainly has been established that gonadotropin as well as par-! \& P& h/ X$ }9 B+ I6 \3 g) a
enteral testosterone administration will produce genital
- a' a/ H8 `3 Kgrowth. Our report shows that the growth of the phallus was6 z+ c  }: m6 U
significantly greater with topical applications than with go-1 b8 k/ |: j! a9 }5 j. M- W
nadotropin, particularly in children less than 10 years old.# N$ y5 n3 }: |3 e) y
The levels of serum testosterone remained similar or lower
* G% b" x  ]2 K/ j. |than with gonadotropin during therapy, suggesting that topi-
2 e3 v1 Z- b5 b. ~cal application produces genital growth by its local effect as
7 U+ W# X: _+ W) @' u8 T0 _well as its systemic effect.
" \) K; q) u, i2 _Review of our patients and their growth response related to$ v1 v  z$ B: z
age shows a greater growth response at an earlier age. This is: K& _, B/ F7 b; ]7 S3 _
consistent with the findings of Wilson and Walker, who
/ |0 m/ M$ _( V- J* \reported an increased conversion of testosterone to dihydrotes-/ [$ F5 |8 x7 U1 c
tosterone in the foreskin of neonates and infants.4 This activ-. Z4 E" d2 {6 g: [7 y+ B! x! Q
ity gradually decreases with age until puberty when it ap-
6 r9 [8 @* F* t4 jproaches the same level of activity as peripheral skin. It may
/ u+ x. Z6 @& n' Iwell be that absorption of testosterone is less when applied at
) R' L# U4 i1 Q9 Pan earlier age as suggested by lower serum levels in children2 K; Y: \# |9 T( O: h7 x! S/ k2 ~
less than 10 years old. This fact may be explained by the! O6 g7 ^: T3 h6 x6 B7 e( C
greater ability of phallic skin to convert testosterone to dihy-
. s# [* D  K  y0 d9 w' ~' ddrotestosterone at this age. Conversely, serum levels in older6 \6 v" j) g: L& x* K" v
patients were higher, possibly because of decreased local" E( J. ^" @  J
667$ }. n1 O8 C0 b+ b' C
668 KLUGO AND CERNY/ g' k$ v( z: s8 [, S" z6 ?
Pt. Age/ C# S  h% u. f( s( `& Y' r
(yrs.)
# }. k' P3 `4 ~, T$ q* bSerum Testosterone Phallus (cm.) Change Length6 R8 j$ s" a& q& s
(ng./dl.) Girth x Length (%)
, D- z5 ^+ D0 F6 X' |& P4, K9 R& d, E# T/ g
8, ^2 b2 x+ ?) f4 T- e
10
& s2 o, t; W: C3 U$ l12
2 J4 _$ y' Z+ K+ k2 o  r17" \# x7 B0 g1 p/ ^% E1 o, X5 J
Gonadotropin
" d, N- }" P9 E' ^8 O* L% Z71.6 2.0 X 3 16.6* D3 B6 q& o; f* ]3 A' h  }) \
50.4 4.0 X 5.0 20.0  A& y: B# l6 D1 I
22.0 4.5 X 4.0 25.0
  X# h, R; b9 j# W84.6 4.0 X 4.5 11.1+ F- r8 J. {# B" W8 t( m) p
85.9 4.5 X 5.5 9.0
$ M/ O$ l2 ~& A8 ^2 n/ uAv. 14.3" N+ }9 N/ k. v
4
: W( F" O& F& \  b7 [. A% }82 U: J* d5 q! `1 w1 K0 T3 P3 W
10' k5 ]$ P/ z* J4 ?) U
12+ I7 M# Q0 `5 a9 t  ]
17
: c7 r# F$ q) R) I$ rTopical testosterone# ^8 C0 |5 H* b# Q
34.6 4.5 X 6.5 85- b# s, L8 N, X: R" I/ Z
38.8 6.0 X 8.5 705 N1 X% l3 Z7 `1 u
40.0 6.0 X 6.5 62.5' b5 i4 R% k2 T1 B' o
93.6 6.0 X 7.0 55.5
: s! f6 N, `; Z7 f& C95.0 6.5 X 7.0 27.2" L& [4 L  ]; d0 B, X8 A
Av. 60.0
' H3 O' [/ C0 V2 t8 L- |$ |available testosterone. Again, emphasis should be placed on
  H, ^4 [5 \9 {1 Q* _: a/ ^: F9 w! xearly therapy when lower levels of testosterone appear to6 ]9 l* {7 L3 v1 Z5 ^
provide the best responses. The earlier therapy is instituted
9 }3 b: s3 e# O$ l2 Rthe more likely there will be an excellent response with low
2 g$ W( C" z0 O8 y5 Hserum levels. Response occurs throughout adolescence as
" Z5 o& l5 i8 u7 V" onoted in nomograms of phallic growth. 7 The actual response
6 N8 {' t# p8 Q/ f2 @to a given serum level of testosterone is much greater at birth- P" Y1 W/ \5 Y; ^/ u! h- u; B% _
and gradually decreases as boys reach puberty. This is most
1 l' T/ I6 C% F  C4 Q  k+ A1 [likely related to the conversion of testosterone to dihydrotes-
! p/ O4 B" p8 N* w6 g+ O. O, L3 Wtosterone and correlates well with the studies of testosterone
1 B0 D0 o# I+ p: ~: T  ~conversion in foreskin at various ages." F0 u9 s$ ]. q6 f' j
The question arises regarding early treatment as to whether) a0 w6 m: \* i1 `
one might sacrifice ultimate potential growth as with acceler-1 x0 k9 B$ ^" ~" v
ated bone growth. The situation appears quite the reverse- o. H7 b0 N& p) s2 H* X
with phallic response. If the early growth period is not used7 {+ M( w) ?! Y* L
when 5a reductase activity is greatest then potential growth! X* M! J0 `3 R
may be lost. We have not observed any regression of growth
! L! e6 t' i4 J, pattained with topical or gonadotropin therapy. It may well
3 D* n) q7 }- z& q* @2 V* ube that some patients will show little or no response to any' g$ \. i! F% Z1 r. f1 @
form of therapy. This would suggest a defect in the ability to
/ l. J4 g  u' K: J5 h4 aconvert testosterone to dihydrotestosterone and indicate that
- S0 }( K) {* u: V9 ~! x! L3 Cphallic and peripheral skin, and subcutaneous tissue should
( P9 F0 u/ e" O. G/ I. Obe compared for 5a reductase activity.
1 e2 M* E( R! ^3 w; EA, loop enlarges to measure penile girth in millimeters. B,
( F) M- A( L4 L7 O8 Q! J# eexample of penile girth computed easily and accurately.8 C: l8 I: v( N5 j
conversion of testosterone to dihydrotestosterone. It is in this
: k  s/ Q6 E8 g$ ?older group that others have noted high levels of serum
3 Y' l! I- Q: dtestosterone with topical application. It would also appear
. i+ G! h: I6 J( gthat phallic response during puberty is related directly to the) C9 a, W6 s9 V6 ^8 q1 z1 n) k; Z, E
serum testosterone level. There also is other evidence of local' h, n1 j1 q& g" T# V
response to testosterone with hair growth and with spermato-
0 L! g/ K8 m" zgenesis. 5• 6
* ^) @& E& }- O' n( f2 WAdministration of larger doses of gonadotropin or systemic1 U; S% J: f  M! w  x/ I' p0 m
testosterone, as well as topical applications that produce
$ M- [- C# L# J# Q( L7 whigher levels of serum testosterone (150 to 900 ng./dl.), will: x4 ^4 e9 \) v9 }/ l) k
also produce phallic growth but risks accelerated skeletal
" S* W4 Z: F# t+ r0 X* r" Umaturation even after stopping treatment. It would appear
/ y; a2 z8 Z% E; q9 Q1 @8 [6 Pthat this may be avoided by topical applications of testosterone
! T, V( K$ |: q* e) H# |0 zand monitoring of serum testosterone. Even with this control
* }/ I/ m) q% I% X$ Q8 Bthe duration of our therapy did not exceed 3 weeks at any. Q( ~" A( _9 ?- r; i
time. It is apparent that the prepuberal male subject may
# |4 S: _1 M' Y! s( _5 g( `suffer accelerated bone growth with testosterone levels near! L. D; R6 m! X" Y/ ~; o& R0 B
200 ng./dl. When skeletal maturation is complete the level of
% l9 N; y0 f: `+ ~5 D5 u; }6 userum testosterone can be maintained in the 700 to 1,300 ng./( X, m/ ~$ Z/ W
dl. range to stimulate phallic growth and secondary sexual
; ?& ^$ G4 G& I$ }: K# vchanges. Therefore, after skeletal maturation parenteral tes-  @, {; D5 B% s5 f2 I
tosterone may be used to advantage. Before skeletal matura-
, F' }* @, B) v) Q/ ?+ Q, g& N/ ation care must be taken to avoid maintaining levels of serum
' k; }1 K7 _; Z5 m3 ztestosterone more than 100 ng./dl. Low-dose gonadotropin
- e2 _* i0 X* [+ v7 [& ]* g  n8 Ydepends upon intrinsic testicular activity and may require
- _, @" S, l$ [/ P) f$ Vprolonged administration for any response.! c: ?6 C* v$ d/ t  b
Alternately, topical testosterone does not depend upon tes-; x0 s9 ?1 M7 b5 E/ ^6 I
ticular function and may provide a more constant level of
% B8 h" c% y3 |1 o" K$ I! v' Q* V! _REFERENCES0 C! w7 Q8 e( M4 O( \; V4 s2 M* c3 P
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,& }$ [) r% Y' Q3 S- K. A
R.: The local application of testosterone cream to the prepub-& g# `& s" Z& }/ Z
ertal phallus. J. Urol., 105: 905, 1971.$ e( Y. w5 B" }# h$ D
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone: ~; n( _4 _5 U2 y+ E1 |
treatment for micropenis during early childhood. J. Pediat.,
+ \5 ~8 I! F) M( ]1 c# n83: 247, 1973.* L" ~/ s( U0 r. T; I
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
. M; x& O' H. ^0 z4 hone therapy for penile growth. Urology, 6: 708, 1975.
* B3 g9 H3 U  n- g7 M, x4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone0 j% t) ~4 G( g- C2 u, d
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 M+ \! r' `% L7 m  m
skin slices of man. J. Clin. Invest., 48: 371, 1969.% u1 M8 N( M' f" b5 Z) i' v
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 r$ ~. z6 R" U* D6 g9 b( G5 Oby topical application of androgens. J.A.M.A., 191: 521, 1965.
" t* n& X$ }" S% _5 P; n6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
$ ~8 u9 Y* ?: eandrogenic effect of interstitial cell tumor of the testis. J.4 q2 g; A$ {2 O9 o: P6 n" T& o
Urol., 104: 774, 1970.' L: ]5 ]6 P, l
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-. n) ~$ J7 p; V$ f
tion in the male genitalia from birth to maturity. J. Urol., 48:
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