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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND8 X# u( Z+ O* I6 a; }
GONADOTROPIN
7 @( j: L4 ?. Z& H* ~RICHARD C. KLUGO* AND JOSEPH C. CERNY
! y- L2 \* t  e6 uFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
( C. r8 V+ Q' G3 a- IABSTRACT
0 l1 g. }# y9 k% A; N  x6 G0 HFive patients were treated with gonadotropin and topical testosterone for micropenis associated
1 U2 F# d! \5 bwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) Y0 @- G0 c/ X( B4 ?' j1 Dtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone9 B% F" @- `, y) N+ l
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent; m& a0 I& d& F  d8 N. F
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent3 ~" G8 H4 V/ O+ a+ m
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average0 ]4 q$ M- O9 I0 Q% ?) [9 m
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ k. y7 _  T2 loccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This6 S/ \- `1 j% R5 r1 j
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile# O  b% g" n* f# T% i5 b
growth. The response appears to be greater in younger children, which is consistent with previ-
" R4 g. g% z/ R" Nously published studies of age-related 5 reductase activity.
# C7 O3 T+ U) ]/ b) Q% L  B4 {  T$ YChildren with microphallus regardless of its etiology will+ O0 Z% _; W$ l
require augmentation or consideration for alteration of exter-# _; K$ K. _& x+ D. g0 ]
nal genitalia. In many instances urethroplasty for hypo-
2 p9 i4 J0 x3 t: q2 H1 \spadias is easier with previous stimulation of phallic growth.& X; Z+ z; j8 f! D6 k
The use of testosterone administered parenterally or topically
, V1 q' x( T$ y& mhas produced effective phallic growth. 1- 3 The mechanism of
6 K6 G: a* |' M8 W4 {1 H9 m0 q- gresponse has been considered as local or systemic. With this) h- e; G! e& \6 @
in mind we studied 5 children with microphallus for response
, w) p5 N% t) i5 a% k+ i% \to gonadotropin and to topical testosterone independently.+ a  n1 @0 B% J9 z
MATERIALS AND METHODS; S# ]6 r1 g- @0 |
Five 46 XY male subjects between 3 and 17 years old were$ I9 \; L8 a+ }- ^, z/ E+ F7 J
evaluated for serum testosterone levels and hypothalamic3 }; W& P9 D  `9 O
function. Of these 5 boys 2 were considered to have Kallmann's
- v6 f' m( U& n/ y, D! g. Csyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-1 N# ~8 J4 q2 |6 m& F' N  u* h6 _
lamic deficiency. After evaluation of response to luteinizing8 z; [6 F4 `4 X
hormone-releasing hormone these patients were treated with# y9 c/ H4 T# L8 e# y
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
7 B# A& M% k8 H) F) S; \6 N. dafter completion of gonadotropin therapy 10 per cent topical# z" r- q7 O0 k' W) p5 E
testosterone was applied to the phallus twice daily for 3 weeks.
' Q) k% }' f" ZSerum testosterone, luteinizing hormone and follicle-stimulat-
* t5 z2 h) A5 B  R( qing hormone were monitored before, during and after comple-1 u) ?! g6 t' g. n6 c% w
tion of each phase of therapy. Penile stretch length was( ]( p* W8 w& ?2 C
obtained by measuring from the symphysis pubis to the tip of
& f" U1 H8 n; ^9 Ethe glans. Penile circumferential (girth) measurements were2 v5 H) c; m+ B) u: H0 k, v% J
obtained using an orthopedic digital measuring device (see
% V7 u8 z* _8 Q1 |4 }( Yfigure)., G8 N: y6 z- L, h: E/ V4 W8 w! \
RESULTS& z' r- ^$ p- O7 a% m: r/ D" r
Serum testosterone increased moderately to levels between, {7 X" a0 Q9 d8 J
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-  M2 j6 F7 N& F3 b. v
terone levels with topical testosterone remained near pre-
% Q2 p- e2 b$ r( M2 V% Gtreatment levels (35 ng./dl.) or were elevated to similar levels
$ M8 G3 S$ W( w. \0 ?' c+ ?, odeveloped after gonadotropin therapy (96 ng./dl.). Higher
! g& \0 f+ S5 o' f, W  Mserum levels were noted in older patients (12 and 17 years old),
8 P- _9 \# T3 r8 W* vwhile lower levels persisted in younger patients (4, 8, and 10% f# e+ {: W1 y2 `: `+ n' H3 ?
years old) (see table). Despite absence of profound alterations9 C2 w! [# b7 _) q  w
of serum testosterone the topical therapy provided a greater# T- N5 t* x2 S1 K( M9 O
Accepted for publication July 1, 1977. ·
$ H/ u4 R* _; }8 v9 f# MRead at annual meeting of American Urological Association,
& A8 o1 y( z: B' M, \Chicago, Illinois, April 24-28, 1977.
. q/ d1 Y( @+ g9 l7 r8 q) C% h* Requests for reprints: Division of Urology, Henry Ford Hospital,
! ^( A4 Q7 h' E8 @. T; W9 \2799 W. Grand Blvd., Detroit, Michigan 48202.3 z) M0 A2 |; E& }8 m
improvement in phallic growth compared to gonadotropin.
3 j5 Z- \% @' j2 `" e0 c( X1 ~8 cAverage phallic growth with gonadotropin was 14.3 per cent  L4 m) @+ r' A9 [
increase in length and 5.0 per cent increase of girth. Topical
3 e* a" a& H4 ]0 @, ?3 ntestosterone produced a 60.0 per cent increase of phallic length
8 a' ]  S6 e- Mand 52.9 per cent increase of girth (circumference). The
6 L) y4 V3 B2 Y# z0 h1 ^response to topical testosterone was greatest in children be-; G9 k+ a: c0 O' H0 s9 h7 L
tween 4 and 8 years old, with a gradual decrease to age 17
8 N7 T2 \! G8 w0 [$ Zyears (see table).
+ K* l) p- {! {! LDISCUSSION! e2 j  t7 ]% G* [3 O& m( U
Topical testosterone has been used effectively by other7 Y) y+ V4 t, `) B- h$ T- o- M- g
clinicians but its mode of action remains controversial. Im-
* z0 a( R. o0 s5 y* imergut and associates reported an excellent growth response
3 d# x0 c1 p' s& @5 }1 @4 Cto topical testosterone with low levels of serum testosterone,5 l+ k# e1 d  I$ F8 g
suggesting a local effect.1 Others have obtained growth re-
  y; T8 N% F, p  @( U/ f* |/ W$ `sponse with high. levels of serum testosterone after topical; G! h8 `5 h( [, R# V
administration, suggesting a systemic response. 3 The use of* h& q: U6 g3 b3 E1 W
gonadotropin to obtain levels of serum testosterone compara-) p( A1 j' G1 Z$ r
ble to levels obtained with topical testosterone would seem to
9 c8 E9 ^# l. F# k: N( L3 y. O6 eprovide a means to compare the relative effectiveness of9 D; x/ f# D5 _' M# `# v% O
topical testosterone to systemic testosterone effect. It cer-- g* k% v8 i: h5 C
tainly has been established that gonadotropin as well as par-! h) X5 e- x7 B) q4 ~/ h3 I
enteral testosterone administration will produce genital
, |: y% p$ N" \" ~, q$ rgrowth. Our report shows that the growth of the phallus was( M$ h5 A8 {. t4 R; M/ q# {
significantly greater with topical applications than with go-
6 c, E3 h$ B0 O; \! _/ T9 ?nadotropin, particularly in children less than 10 years old.) h8 ^* R" v7 G/ d" ^, z
The levels of serum testosterone remained similar or lower
& }+ l  x7 U* I) d$ x6 T, Xthan with gonadotropin during therapy, suggesting that topi-$ V. \4 h7 C0 j4 x4 T" K  Z
cal application produces genital growth by its local effect as$ P6 W0 X2 q; L/ V* U) @% a% ~, M
well as its systemic effect.; H( }" A% g* r
Review of our patients and their growth response related to  z" V9 ?  f* j
age shows a greater growth response at an earlier age. This is
/ y+ u. N; P7 [consistent with the findings of Wilson and Walker, who
  h2 l5 u" Q4 P( Z, A2 q9 ureported an increased conversion of testosterone to dihydrotes-) H8 G3 O3 f% Z: F% T1 `9 z4 Q
tosterone in the foreskin of neonates and infants.4 This activ-
' W" L$ D) u3 s8 W( Yity gradually decreases with age until puberty when it ap-; {$ G/ _2 B4 D2 e8 g- e
proaches the same level of activity as peripheral skin. It may1 o2 j5 j# g( U) P5 a
well be that absorption of testosterone is less when applied at
. u+ Z2 T. B: R( m4 G8 ?an earlier age as suggested by lower serum levels in children
0 O, E% A; c: |, L. qless than 10 years old. This fact may be explained by the
. a# f' g+ B# W. lgreater ability of phallic skin to convert testosterone to dihy-, C9 W' T' c# {0 q, l
drotestosterone at this age. Conversely, serum levels in older
+ _8 Q* y( E# ]' n- u# \patients were higher, possibly because of decreased local) x; B7 x' n2 R( H  R: b
667
2 z& {' n% g5 m0 Y9 ~2 f: i668 KLUGO AND CERNY
& ^: ?6 }# L" {9 ~  uPt. Age$ O% U) m* X6 q  U# D
(yrs.)
6 L5 i  N6 L4 ?& C6 T5 U7 [Serum Testosterone Phallus (cm.) Change Length& Q0 I: Y- `* O3 F/ W
(ng./dl.) Girth x Length (%)
3 J' e$ P: `# g1 F40 a3 Q) R2 V; W* ~
89 E9 B( J' v" w
10
, p8 f% ?* S4 t3 e4 r" s12
! j/ e$ z: P3 r  ~- w9 L2 n! u17% T! O( l: T" x- X* s
Gonadotropin
& r7 F" @+ a4 }8 f5 l3 o, u71.6 2.0 X 3 16.61 }; e3 L5 b" M( n1 L* ^+ @8 l* G
50.4 4.0 X 5.0 20.0" Y; a3 f' g9 N/ _6 v: T
22.0 4.5 X 4.0 25.01 \8 H* A+ Z5 F: I- e
84.6 4.0 X 4.5 11.1
, k3 e4 L9 ~5 M( ^  V85.9 4.5 X 5.5 9.0
4 ^' t4 X! {# e: ^, qAv. 14.3
& e) H7 T! p( P  h! i; @43 v: ?: T9 G1 W
8
. }8 r& h% ~! [. T; @  M1 W10
- R/ Y  ]4 O  ~$ X12# R9 l+ ^7 {2 n1 ~& [/ ?2 f( u
17  H+ c& i& \4 L! z
Topical testosterone
) k. V7 {9 S$ n4 E6 A& e# c4 V34.6 4.5 X 6.5 85: ?( `6 G9 T- r3 r! D  N, b9 M
38.8 6.0 X 8.5 70" d# w. u% j* L4 ]  B9 V
40.0 6.0 X 6.5 62.5
. o; @9 A9 g, ]: ~& Q93.6 6.0 X 7.0 55.5
. x1 a, l8 P  o" y9 }7 i* T95.0 6.5 X 7.0 27.2. h$ x; V3 ^. c* W/ o7 U
Av. 60.0
8 u& j! q! U) |$ S+ ^% _. ^available testosterone. Again, emphasis should be placed on
! K- I; P1 y2 U  v; Uearly therapy when lower levels of testosterone appear to% m" D3 s4 B7 S2 t1 o2 s4 q- f( m. J
provide the best responses. The earlier therapy is instituted
* s( a8 j/ ]0 ~. {3 u; r4 @the more likely there will be an excellent response with low$ `* K! {- _3 s, h; [! X, N: R
serum levels. Response occurs throughout adolescence as" v7 k; f- k6 g5 x$ j; {
noted in nomograms of phallic growth. 7 The actual response6 ~& c# {0 o" t6 k
to a given serum level of testosterone is much greater at birth
; l; X) Y5 T0 ^4 M1 f- t* vand gradually decreases as boys reach puberty. This is most
3 G* X* s8 T3 C' k" X$ |5 [& tlikely related to the conversion of testosterone to dihydrotes-1 W6 f* h+ o. o- y: q) Z7 ]
tosterone and correlates well with the studies of testosterone
" z* r% ?: d( d( Q0 N- F1 Sconversion in foreskin at various ages.
4 [/ g3 N; D* P5 ?% b, S1 KThe question arises regarding early treatment as to whether
5 B2 H6 ~$ s& }4 uone might sacrifice ultimate potential growth as with acceler-
8 L: Z' T) a9 i, ]ated bone growth. The situation appears quite the reverse, E  E5 s( A, g+ m) H0 Y& S
with phallic response. If the early growth period is not used
) k4 H: z; w) V: v8 X5 rwhen 5a reductase activity is greatest then potential growth
0 O  Y% V& n$ Z' Pmay be lost. We have not observed any regression of growth
7 H% z* P3 _# y$ n' R6 y2 Lattained with topical or gonadotropin therapy. It may well$ B+ o; P0 ^) `# A4 c" y
be that some patients will show little or no response to any
) d- r- S% [1 x7 m* oform of therapy. This would suggest a defect in the ability to) `5 {+ b; J  b# R* m! @) K
convert testosterone to dihydrotestosterone and indicate that! ?) c5 h. C3 {9 q
phallic and peripheral skin, and subcutaneous tissue should8 C/ }- L' |  U- X
be compared for 5a reductase activity.: k' W" j; W+ E2 {+ Z8 n
A, loop enlarges to measure penile girth in millimeters. B,
1 h% H& v4 J: qexample of penile girth computed easily and accurately.
8 g2 B1 `8 ^, Tconversion of testosterone to dihydrotestosterone. It is in this! z% `5 {" `: \; h$ e5 M3 K, g6 w
older group that others have noted high levels of serum
* k( @, C' j7 Q  qtestosterone with topical application. It would also appear$ h; M, K4 Z1 g1 k# X- S: f7 ^
that phallic response during puberty is related directly to the# q/ @  ~0 i% ?4 q* U) K9 F
serum testosterone level. There also is other evidence of local. A3 H9 Y& ?% k$ w0 l& @7 }
response to testosterone with hair growth and with spermato-) D3 E6 X3 u% h5 T
genesis. 5• 6
5 ~6 L' U3 r. r2 G# D1 ~Administration of larger doses of gonadotropin or systemic2 L/ y$ B3 @/ @: l* y
testosterone, as well as topical applications that produce
$ {/ J6 _5 m2 r/ Z9 jhigher levels of serum testosterone (150 to 900 ng./dl.), will7 r/ K% r  G3 d; u. y4 P0 E
also produce phallic growth but risks accelerated skeletal  T/ m4 c0 `3 @  m' |
maturation even after stopping treatment. It would appear6 O  R; R' l# O4 n+ Q
that this may be avoided by topical applications of testosterone1 r! F: I2 [8 U7 @
and monitoring of serum testosterone. Even with this control
* C. E2 i/ j+ P- y$ z6 x- N) {7 J; _, Mthe duration of our therapy did not exceed 3 weeks at any
1 v* u5 K1 S5 M% V' Q3 ctime. It is apparent that the prepuberal male subject may
0 C! @/ z* m1 n" ~5 d) v0 \/ xsuffer accelerated bone growth with testosterone levels near' m* s4 o) f- T- u( b
200 ng./dl. When skeletal maturation is complete the level of( k) P3 }( x4 x
serum testosterone can be maintained in the 700 to 1,300 ng./0 X1 v. m; s0 z" H3 x5 r
dl. range to stimulate phallic growth and secondary sexual. R2 C& F# H3 F( D0 Y, T2 X' v
changes. Therefore, after skeletal maturation parenteral tes-' z4 C3 ]( Z, b# L7 |* z) ]
tosterone may be used to advantage. Before skeletal matura-' d# |5 i+ m; J7 a4 A! y, n5 h
tion care must be taken to avoid maintaining levels of serum
2 b. y8 e  `3 U, W' f6 Q, k5 Vtestosterone more than 100 ng./dl. Low-dose gonadotropin
* e/ ?  ?  k9 w/ n' X: Tdepends upon intrinsic testicular activity and may require- i% S* O1 @7 E3 l
prolonged administration for any response.
' u2 A; f: o# ^' [3 K4 m3 Y6 KAlternately, topical testosterone does not depend upon tes-
5 ]$ a) a' ~0 Q: f: ?" b4 {! e: Jticular function and may provide a more constant level of
" V/ D" E5 C5 BREFERENCES( l% H, I2 g3 u5 t& g' d
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
4 p+ g- Q9 v+ o3 e) z4 MR.: The local application of testosterone cream to the prepub-
; K  P9 {! [! w  dertal phallus. J. Urol., 105: 905, 1971.
! m! J9 M9 N; J. T, C& Y: L2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone8 e  O/ S4 j3 X1 e7 c1 R( O9 u
treatment for micropenis during early childhood. J. Pediat.,8 ^0 d" V' y6 l& f# c5 v
83: 247, 1973.
- J7 h( ]6 g* A( H5 K) j. ]3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
5 @/ f9 H+ ?$ f! F) u" a( @. m! ~one therapy for penile growth. Urology, 6: 708, 1975.+ ~& ~) T4 D6 [6 k- b  I- a' z
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 q) W4 i% ]5 z$ ]9 c! e
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% q1 a9 u0 ]) ^% [" d
skin slices of man. J. Clin. Invest., 48: 371, 1969.
/ h4 [; e. Z( C: t# l5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth6 u2 {! Z, B% i0 V) _( y
by topical application of androgens. J.A.M.A., 191: 521, 1965.1 C/ H7 x0 c9 E6 E/ _
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local1 J! c' \/ v( _7 R& q5 T
androgenic effect of interstitial cell tumor of the testis. J.1 x3 P* [; f( S. h( R; O
Urol., 104: 774, 1970.
8 @4 \+ L- c7 ^* S6 f; [! _4 ~7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-. g+ F- P  k! K
tion in the male genitalia from birth to maturity. J. Urol., 48:
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