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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 t/ c( D/ n; O6 P, o0 X, X& O9 I
GONADOTROPIN
5 ~8 l3 P; B" w! @% U' @+ q' nRICHARD C. KLUGO* AND JOSEPH C. CERNY
- U/ L1 S, W; cFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan) q4 H4 h# M9 \) W  K% \, g
ABSTRACT, r# Z) d, M4 F; K1 Y' p, f% o
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
$ l3 H9 x5 Z$ Nwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-% E# q8 s2 w! O6 t/ K" ?
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
% D5 s( [% O" l/ x. N4 _cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent/ v3 m- k/ h5 |1 h" b: q7 e# m0 `! z
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent* G$ V1 y8 C1 [6 w# z" O6 a+ Q
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ [0 P7 R+ w+ a0 f0 @- I6 c1 ~; ]increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
; i. H+ w8 W& z2 ]: I. V" p2 joccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This$ X" ^# X8 ^& \8 e: b
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
9 u: @. G  q( n, y9 I% m/ fgrowth. The response appears to be greater in younger children, which is consistent with previ-$ b' d4 }; F5 [, O/ l( v, D
ously published studies of age-related 5 reductase activity.% E! c9 f# ?: N$ A( x: `: p
Children with microphallus regardless of its etiology will
+ w' K8 s/ }6 I. W5 t' Mrequire augmentation or consideration for alteration of exter-2 N) `# R# S3 v: ~
nal genitalia. In many instances urethroplasty for hypo-: ~0 ?7 Y' q+ d4 T0 N
spadias is easier with previous stimulation of phallic growth.
  X2 H# J* @% B" fThe use of testosterone administered parenterally or topically
2 S' e9 N# w* ]& {9 Vhas produced effective phallic growth. 1- 3 The mechanism of, q' ~- I( x" P# U& i: S- e7 H
response has been considered as local or systemic. With this
  a" r& y/ k8 B8 u% H  G4 hin mind we studied 5 children with microphallus for response
* K$ e4 e+ p" Nto gonadotropin and to topical testosterone independently.
5 t9 Q8 M- N( }' Q2 g0 |7 ~MATERIALS AND METHODS
' x" m. h) G# c' X$ o4 c6 VFive 46 XY male subjects between 3 and 17 years old were
2 K* K/ o1 E! {. mevaluated for serum testosterone levels and hypothalamic6 H7 X0 s- }% U  j2 m2 o  |
function. Of these 5 boys 2 were considered to have Kallmann's# ~1 K& d5 T$ F
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' u* M$ B2 y- G- ^1 ]) j$ `lamic deficiency. After evaluation of response to luteinizing
' A3 c0 ?5 Y% }7 Z* {" Zhormone-releasing hormone these patients were treated with/ R* m5 x4 P9 {* [& [
1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 i  w: \  Z& m' r. t9 p; a
after completion of gonadotropin therapy 10 per cent topical3 N/ K# y; Y! ]( t9 D' Y5 P, ^$ T
testosterone was applied to the phallus twice daily for 3 weeks.
) V. b1 m9 {4 USerum testosterone, luteinizing hormone and follicle-stimulat-. ]: s) |, H3 r
ing hormone were monitored before, during and after comple-6 K" f$ d* Z, K# k: O9 [7 Q
tion of each phase of therapy. Penile stretch length was
. c6 h7 w1 b: w4 ~) G3 X/ Aobtained by measuring from the symphysis pubis to the tip of
: G# K0 S- d6 E2 m# b  Tthe glans. Penile circumferential (girth) measurements were
; K. Y- J5 l; A2 ^' a/ |obtained using an orthopedic digital measuring device (see/ i( _- _( A# L% q+ J9 ~) a
figure).
4 ?) x1 C& k6 R  ZRESULTS
6 P- L/ Q( s# m5 f0 l+ ySerum testosterone increased moderately to levels between
5 R# x/ ?$ X) p3 f+ `7 v50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-9 K9 ]0 O! I6 T; j% I
terone levels with topical testosterone remained near pre-6 v, n5 c; A  f: c- L6 b1 L, Y
treatment levels (35 ng./dl.) or were elevated to similar levels
$ [6 N! d% w' x1 Q: }$ zdeveloped after gonadotropin therapy (96 ng./dl.). Higher
( \  {0 H  {1 V: Gserum levels were noted in older patients (12 and 17 years old),
4 U6 ]" T+ L$ Q, W7 I  F" vwhile lower levels persisted in younger patients (4, 8, and 10
# k- N3 J; @* _3 |years old) (see table). Despite absence of profound alterations
' _0 r$ t1 h( F, V  J. S# Q; [of serum testosterone the topical therapy provided a greater
; g! L, m) x: P1 O  t) P7 @Accepted for publication July 1, 1977. ·6 o( b- F  V% }! q' L
Read at annual meeting of American Urological Association,
+ u4 ~# c( X% wChicago, Illinois, April 24-28, 1977.& P: k) g3 i, [8 N0 {$ l2 W* O
* Requests for reprints: Division of Urology, Henry Ford Hospital,  V6 G# P) H& p. `1 \+ @; \' O8 e
2799 W. Grand Blvd., Detroit, Michigan 48202.
: V( d" y3 P/ }5 Z9 aimprovement in phallic growth compared to gonadotropin.0 A6 B3 ~% U4 [; i3 v1 N/ `) i1 W- T
Average phallic growth with gonadotropin was 14.3 per cent
% _9 ?" R& B# r: ^' n* [increase in length and 5.0 per cent increase of girth. Topical
+ f( {. X6 A* M- h. V. Ytestosterone produced a 60.0 per cent increase of phallic length" \# ?) o/ ]4 q& u3 G
and 52.9 per cent increase of girth (circumference). The
. ~( r# G3 @$ y. I- Cresponse to topical testosterone was greatest in children be-6 A! F! f, W% ^6 |$ f8 I1 `; y
tween 4 and 8 years old, with a gradual decrease to age 17! ]% h/ _% s8 }% T* L
years (see table).  V' c" P, L: |( T9 N: [
DISCUSSION
' n) v1 x3 @; X: f* o. `Topical testosterone has been used effectively by other
' _5 i7 ], O, G% ^- w9 Tclinicians but its mode of action remains controversial. Im-
; H9 ~# ~% H9 X( J  Y7 C- wmergut and associates reported an excellent growth response  ]# t7 B( D% V( r
to topical testosterone with low levels of serum testosterone,
3 f+ q+ q( H4 G" csuggesting a local effect.1 Others have obtained growth re-. F5 A+ s, K  x) `, c4 D% z- F
sponse with high. levels of serum testosterone after topical7 t) M4 Q- G( t; B
administration, suggesting a systemic response. 3 The use of4 N& j6 i3 ^9 g% b. M' s
gonadotropin to obtain levels of serum testosterone compara-* u$ Q- |' |6 I! d7 O7 g
ble to levels obtained with topical testosterone would seem to
, g4 G, f5 E$ {2 {1 m* ~( B% ~provide a means to compare the relative effectiveness of
/ h% L9 {, m* o% W7 w9 P& btopical testosterone to systemic testosterone effect. It cer-
, Q2 [8 V& p$ [7 t* Utainly has been established that gonadotropin as well as par-- E6 [* J" e6 w! P' D, t
enteral testosterone administration will produce genital  y4 X8 V% M. O# c# O! p$ a
growth. Our report shows that the growth of the phallus was& @4 x/ `2 i! J- s
significantly greater with topical applications than with go-
8 k- ?/ I' c: M- j& lnadotropin, particularly in children less than 10 years old.9 g+ c8 w2 u. `/ N
The levels of serum testosterone remained similar or lower+ G5 e( T$ q  c- p
than with gonadotropin during therapy, suggesting that topi-% B' c6 o, c# ~$ X& ^; r
cal application produces genital growth by its local effect as, }5 e8 p* V3 X& x2 w2 a- I4 M
well as its systemic effect.
  i3 @/ I8 ~$ X2 f$ N2 s  F  mReview of our patients and their growth response related to$ V! }  u7 q% p# c" T
age shows a greater growth response at an earlier age. This is' R. y2 p" V6 i' m
consistent with the findings of Wilson and Walker, who1 j4 _4 G0 z# u8 i% o  f* G4 w
reported an increased conversion of testosterone to dihydrotes-# K. u; A# w& Z
tosterone in the foreskin of neonates and infants.4 This activ-
5 m* |3 a: R6 Rity gradually decreases with age until puberty when it ap-
: k, M; s# ]: `- A6 _proaches the same level of activity as peripheral skin. It may# `' b0 X) e, ]$ m( n$ k7 d
well be that absorption of testosterone is less when applied at5 ~: H# f2 B, ]
an earlier age as suggested by lower serum levels in children3 J0 s" r& T) Q9 x% L8 z! @; V9 |
less than 10 years old. This fact may be explained by the  e8 G9 i: y# G$ g- x4 L0 B
greater ability of phallic skin to convert testosterone to dihy-$ ~. U3 T! D0 t, D% k
drotestosterone at this age. Conversely, serum levels in older
0 q# J8 C! O+ d3 qpatients were higher, possibly because of decreased local
7 X* ^" H0 s- K. V1 B; P) R) s667
& g. ]1 U' {7 T6 v5 _668 KLUGO AND CERNY+ \' ~/ S9 y6 c% G
Pt. Age7 ~' I8 R% a: I  U% p9 N# Y1 e
(yrs.)( R+ @" O( q6 _0 S
Serum Testosterone Phallus (cm.) Change Length
( _/ C; X* }$ a(ng./dl.) Girth x Length (%)
1 W3 z# }+ g7 X  T6 K4
# y* R0 S! _' g! y) _$ [( g8
7 J, Y4 U" u/ G! G/ T  ^10
7 B) x$ `; F+ v' u0 |2 v12
) }; T' a, B8 e' T+ _, J17
/ f( i& u$ Y: Z$ p/ t9 T4 f! JGonadotropin
: m: P6 |' H' V& W4 d71.6 2.0 X 3 16.66 o1 {4 y) \# j2 h8 b
50.4 4.0 X 5.0 20.07 X% j7 D0 ?5 g4 N  r
22.0 4.5 X 4.0 25.0
: e  q5 ~. t# t, Y; K# g0 z# F84.6 4.0 X 4.5 11.1
% e6 g$ S. z2 z# U0 c, h: ?+ q( c85.9 4.5 X 5.5 9.0* V$ H. g9 k, U4 ^& k
Av. 14.32 e; }4 g5 K5 V* Z+ s( J4 v
4
# Q: G  X' P( w5 t& k8
5 o7 B. E/ K) W8 Z" X8 s; M10% q& N! J' U  g9 u
12
8 ^1 U; w0 Q, Y& j8 l8 _17' ^8 @/ k$ Y1 f) V7 A# U
Topical testosterone
- R9 J8 J6 x. A4 C. ?+ w34.6 4.5 X 6.5 85! I8 S3 u5 [: i5 m& K( C0 c
38.8 6.0 X 8.5 70
. q& U5 O2 G  I; @4 Y40.0 6.0 X 6.5 62.5% }% Y1 j0 n, f7 r# c
93.6 6.0 X 7.0 55.50 C2 V1 f' k4 p
95.0 6.5 X 7.0 27.2
2 X! P. X* F% a8 Q: j' `$ P& EAv. 60.09 W" A, J  E* i/ v9 v( y
available testosterone. Again, emphasis should be placed on7 O) C" o! G' v5 \" ]
early therapy when lower levels of testosterone appear to  n8 N! z: S8 |$ M' m3 |
provide the best responses. The earlier therapy is instituted
* @+ S1 L5 E8 A, uthe more likely there will be an excellent response with low
4 S! s2 m% {( r+ M; qserum levels. Response occurs throughout adolescence as! n% h0 G& ]9 [. L. w8 `
noted in nomograms of phallic growth. 7 The actual response0 A% z* n# B1 R5 {, R, V+ q
to a given serum level of testosterone is much greater at birth
) F$ K3 a& `$ ]: _, {' W; J, ]* jand gradually decreases as boys reach puberty. This is most
& i" s3 \; k" O# L* K0 elikely related to the conversion of testosterone to dihydrotes-
3 }2 L& w0 n* I" Rtosterone and correlates well with the studies of testosterone# {( C; K9 F) s  G
conversion in foreskin at various ages.5 R# t) ^  f. G
The question arises regarding early treatment as to whether
  h8 Q9 t8 i  O7 }3 @; V! N/ bone might sacrifice ultimate potential growth as with acceler-
4 a6 g( Y" R- {6 e! M2 rated bone growth. The situation appears quite the reverse
2 ?4 w" Y! w3 N0 w. _) L; ewith phallic response. If the early growth period is not used; X- i& `- {- Q$ }9 d$ H; M, @
when 5a reductase activity is greatest then potential growth
: p/ Q5 W  ]3 I6 }& S0 }7 rmay be lost. We have not observed any regression of growth! @, S+ w/ r" h! D& _2 y
attained with topical or gonadotropin therapy. It may well
4 A  e/ B- K1 \0 Q* g; gbe that some patients will show little or no response to any; Z- m/ f- n8 A1 Q* {. d, m, H( u1 `
form of therapy. This would suggest a defect in the ability to
; p0 u: ^2 Q" D3 y( d+ B/ @  `convert testosterone to dihydrotestosterone and indicate that
" j$ c% |  t, ~phallic and peripheral skin, and subcutaneous tissue should0 V+ x- |4 I+ b+ y( O& C. a/ M- _$ ]
be compared for 5a reductase activity.
7 R2 `$ `: @" t  @+ `% y" P& cA, loop enlarges to measure penile girth in millimeters. B," L9 D1 R. `5 }4 P. W4 ]
example of penile girth computed easily and accurately.
' O* h4 n+ x: |conversion of testosterone to dihydrotestosterone. It is in this1 C( e, X7 X5 p- d" ~: V; A6 v" {
older group that others have noted high levels of serum
) e) i5 ]1 Q; i* b0 V7 Btestosterone with topical application. It would also appear
# B5 r( c3 U0 Mthat phallic response during puberty is related directly to the6 o4 M; ?" ^2 R
serum testosterone level. There also is other evidence of local& t: N- G6 H  U  A0 v/ e7 m: P& l
response to testosterone with hair growth and with spermato-" N( g+ N3 x9 W6 _% d7 G
genesis. 5• 6- z2 B+ }- ?) U' g# r/ A  S
Administration of larger doses of gonadotropin or systemic
4 E% m- c3 ~+ {$ D; U1 t2 htestosterone, as well as topical applications that produce: P0 \$ a" V; e# c* w
higher levels of serum testosterone (150 to 900 ng./dl.), will
% {! y0 k2 T! f8 q4 e5 M: ealso produce phallic growth but risks accelerated skeletal% M/ z5 Z; c3 f3 B+ {6 w: X) h# v
maturation even after stopping treatment. It would appear! y2 o) Z/ f6 ~4 f( a6 _
that this may be avoided by topical applications of testosterone
5 C9 v0 o* `7 O- f" f5 o& z9 Xand monitoring of serum testosterone. Even with this control2 S9 C! ]) G( w7 @) F0 x# K
the duration of our therapy did not exceed 3 weeks at any
3 N- q, v( m4 |# N# @1 m1 V1 T  ptime. It is apparent that the prepuberal male subject may
5 k4 c8 s$ Q! e  n. ?1 |suffer accelerated bone growth with testosterone levels near( n; F, r8 b7 L# s4 d
200 ng./dl. When skeletal maturation is complete the level of
) B$ V0 h6 F1 P) gserum testosterone can be maintained in the 700 to 1,300 ng./8 i7 y" j/ {. W% I/ E- G* N: ?
dl. range to stimulate phallic growth and secondary sexual0 x3 J2 @/ Q8 ~- z; F0 E
changes. Therefore, after skeletal maturation parenteral tes-+ m& ?1 C0 `. o- I# H1 g  _- m/ Y6 v
tosterone may be used to advantage. Before skeletal matura-/ o% L( N1 T3 `5 Z' w
tion care must be taken to avoid maintaining levels of serum
/ t# p$ M0 x8 C$ g: K7 p- t& O7 O5 Etestosterone more than 100 ng./dl. Low-dose gonadotropin# a$ w0 {- l! k8 m' D+ t
depends upon intrinsic testicular activity and may require0 K4 Y* ]$ V  |. F
prolonged administration for any response.
1 i7 `+ R6 l! BAlternately, topical testosterone does not depend upon tes-. n/ A1 g/ @. y
ticular function and may provide a more constant level of
1 E$ `' W# n& l+ _" C( U: W9 {REFERENCES+ k5 K: U$ z8 V
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
0 E; W1 Q3 u7 b( l  m5 t' C: lR.: The local application of testosterone cream to the prepub-
1 s$ c: }( q/ p  S$ P% pertal phallus. J. Urol., 105: 905, 1971.
* n' Q) y7 F0 E, H6 C* n, }2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) w0 h1 m; N' N& [4 Xtreatment for micropenis during early childhood. J. Pediat.,/ k+ W  N: C5 s8 `( x! `& H) Z% e
83: 247, 1973.
6 D( g& J2 c: c; q8 ^3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-2 ]& l6 ~9 v1 Y2 @7 Y3 U& j4 U
one therapy for penile growth. Urology, 6: 708, 1975.
  f$ t' G1 z& Y' \4 f4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 b: I% ?2 A/ G* n$ r' z9 S
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
/ Z2 g8 W. K$ v. K' Yskin slices of man. J. Clin. Invest., 48: 371, 1969.2 I2 f9 K" c8 f8 S) p; ?. l+ S
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
, H5 l" Z* U4 ^! {by topical application of androgens. J.A.M.A., 191: 521, 1965.) x/ [: \. [( A4 U
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
) H" I1 z$ ^! F5 |6 |% r1 N1 u+ a" Nandrogenic effect of interstitial cell tumor of the testis. J.
- ]  ]4 n& k& @+ J5 L; {Urol., 104: 774, 1970.: B$ l- H& R5 c
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-2 D' f- Y( d9 @. m
tion in the male genitalia from birth to maturity. J. Urol., 48:
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