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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND+ p# Z  X2 Z/ m8 x) b+ t! z+ A
GONADOTROPIN, w7 `& X1 U, f; ~. o! G
RICHARD C. KLUGO* AND JOSEPH C. CERNY
3 v; y! R) R' q$ LFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan9 Z4 d6 i/ f  r" l) \$ n/ H" f' @
ABSTRACT
) t9 w- I7 p- I+ n; ^/ eFive patients were treated with gonadotropin and topical testosterone for micropenis associated4 G7 \6 [$ \& C. C
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
7 h, ^) T0 w  l0 f6 Dtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
% d( K' ^2 h' q, R0 ocream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent8 ~% o( N+ {2 B
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent  c3 E4 S( @% X" e  I
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average5 |: ?1 T2 X; [1 d% P1 W" ?
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
) \% J1 I- J* |; Z7 Boccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
0 L$ ~( `) E  ~7 I  pstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile8 w1 |$ C. ^/ q; i
growth. The response appears to be greater in younger children, which is consistent with previ-
6 J3 B" s, x' P8 W* D1 wously published studies of age-related 5 reductase activity.2 E% ~& d* G9 M1 W( P- ~
Children with microphallus regardless of its etiology will
& ~' I. J1 T$ ?2 [$ K$ C/ Prequire augmentation or consideration for alteration of exter-
% \2 I. B6 n6 L9 Pnal genitalia. In many instances urethroplasty for hypo-
. V0 T, J2 I( w0 U- b4 O5 i* }  {spadias is easier with previous stimulation of phallic growth.
$ x, G. M6 t5 M0 \) lThe use of testosterone administered parenterally or topically  N7 H6 @' S! \0 N$ L9 Y4 g8 l
has produced effective phallic growth. 1- 3 The mechanism of! T7 q, I3 m/ e7 }+ S, ]
response has been considered as local or systemic. With this
- Y1 Z2 _3 Q; ~  R( Y2 Y8 R- Tin mind we studied 5 children with microphallus for response
) `, E( U) V/ V) A9 mto gonadotropin and to topical testosterone independently.
& c5 ?# G, ^, p+ mMATERIALS AND METHODS$ _7 y$ G2 h+ U* U8 s
Five 46 XY male subjects between 3 and 17 years old were
' y0 M7 T8 M' B( [evaluated for serum testosterone levels and hypothalamic3 e! C5 |, k& w3 d& f$ `
function. Of these 5 boys 2 were considered to have Kallmann's9 _: _  T; q) V* G
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-$ s' z" F& z, b3 k) H
lamic deficiency. After evaluation of response to luteinizing
0 p0 }/ D6 ^. l/ }hormone-releasing hormone these patients were treated with# y3 y+ m& Q$ s  e7 y4 P0 C8 T, F. A
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
8 d/ ~9 p7 @  e9 b  Z. l' Mafter completion of gonadotropin therapy 10 per cent topical. h, q$ R7 R! L( J
testosterone was applied to the phallus twice daily for 3 weeks.
. D6 V3 d1 C" w- k6 h. ~Serum testosterone, luteinizing hormone and follicle-stimulat-+ n7 k8 }" `9 V
ing hormone were monitored before, during and after comple-" S8 b( T8 g# a* t. ~
tion of each phase of therapy. Penile stretch length was
2 ^4 K; O( T/ x0 y* v! Dobtained by measuring from the symphysis pubis to the tip of
; H2 p9 A; u) P. Jthe glans. Penile circumferential (girth) measurements were
, ]* O5 {9 |) t5 cobtained using an orthopedic digital measuring device (see; X7 H  v* o/ k/ R) o
figure).
4 L* J. R$ J; D3 h+ URESULTS( S4 l+ H% }5 {. t2 P# |! @; @
Serum testosterone increased moderately to levels between: r1 Y) u' A9 o. z9 v0 S( i
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
( P' G" Q6 [! O$ L+ h( O) Aterone levels with topical testosterone remained near pre-1 B# S  ~: M9 U+ ]
treatment levels (35 ng./dl.) or were elevated to similar levels  e3 Q& G' q- ~! }, a- ]2 g
developed after gonadotropin therapy (96 ng./dl.). Higher/ X. E& U5 ?* N7 @0 n  m
serum levels were noted in older patients (12 and 17 years old),. ]7 f! I# X- O" `% z+ W
while lower levels persisted in younger patients (4, 8, and 10) l+ Q. x, l0 O$ A% m
years old) (see table). Despite absence of profound alterations6 @/ }9 E# c2 O  d4 ^) d/ R
of serum testosterone the topical therapy provided a greater
1 p' z' [( [5 D+ t, S+ uAccepted for publication July 1, 1977. ·
" `* |! d" \& [- ?Read at annual meeting of American Urological Association,; \& q$ c+ g$ U- [" L
Chicago, Illinois, April 24-28, 1977.
8 {: r! c' |; S: I1 p* Requests for reprints: Division of Urology, Henry Ford Hospital,+ \, U) K: N5 ]3 n
2799 W. Grand Blvd., Detroit, Michigan 48202.
0 Y9 I! N9 Q& w+ z, s, mimprovement in phallic growth compared to gonadotropin.
6 |# J" D7 g% Y. gAverage phallic growth with gonadotropin was 14.3 per cent
  I/ l  L+ N* N) `increase in length and 5.0 per cent increase of girth. Topical/ ]1 I( W- X" F+ T" K
testosterone produced a 60.0 per cent increase of phallic length6 w  u6 q- i/ d7 {% Q9 W# y
and 52.9 per cent increase of girth (circumference). The
; i8 b6 b0 ^; E( l: J1 k( aresponse to topical testosterone was greatest in children be-6 B, t5 _: s9 e* }, [
tween 4 and 8 years old, with a gradual decrease to age 17
! ^0 `9 q/ B( h9 D6 Fyears (see table).- }2 d" ]* ^3 y& `% k
DISCUSSION! u7 T( ]% p7 `2 ~
Topical testosterone has been used effectively by other! y% W, r8 {' q3 h" F- i5 B7 ^
clinicians but its mode of action remains controversial. Im-
4 }" A! Q0 e% t# y1 C0 Wmergut and associates reported an excellent growth response
6 j3 J% G8 c- x; w) P! @3 ?% Uto topical testosterone with low levels of serum testosterone,1 i5 g. ?- `9 G  ~' ?9 @+ P  d
suggesting a local effect.1 Others have obtained growth re-
* y; U$ O& h( `9 k% o. u$ I. _sponse with high. levels of serum testosterone after topical
1 Q# y, Z4 @) G, _& C, F9 K1 q1 Iadministration, suggesting a systemic response. 3 The use of
$ q: l7 _' e: v9 tgonadotropin to obtain levels of serum testosterone compara-  h  ^4 s' t+ v( s) J
ble to levels obtained with topical testosterone would seem to
. U5 n8 ]% B1 Jprovide a means to compare the relative effectiveness of8 j: |4 Q! C' x
topical testosterone to systemic testosterone effect. It cer-
" @7 F5 }7 M' B- G1 K3 u) s, o: z- Ntainly has been established that gonadotropin as well as par-* O2 ]0 y1 w$ C  q' S) Y& ?
enteral testosterone administration will produce genital1 |; m! L2 z3 L9 A3 Q. O/ H
growth. Our report shows that the growth of the phallus was7 M6 ~0 e" @- A% M
significantly greater with topical applications than with go-
# Q- q% Q7 c" Ynadotropin, particularly in children less than 10 years old.3 |% M! ~. g2 c- G
The levels of serum testosterone remained similar or lower
& K' v" Q& Y, y0 r) }+ bthan with gonadotropin during therapy, suggesting that topi-  G/ |0 Z( r( U, }. j
cal application produces genital growth by its local effect as/ j) j. P( P1 o: e
well as its systemic effect.
2 |; a5 n9 e5 P  ]Review of our patients and their growth response related to* V# A4 }  J( t7 O
age shows a greater growth response at an earlier age. This is0 d& C% @& b7 g; g  [
consistent with the findings of Wilson and Walker, who
- l9 N2 c! v0 K6 V) o3 z" Freported an increased conversion of testosterone to dihydrotes-
; N" e0 r+ t+ G: K8 G6 g; rtosterone in the foreskin of neonates and infants.4 This activ-
' R( I% Y- `$ P1 Lity gradually decreases with age until puberty when it ap-3 Y7 R3 _4 y+ g' t9 I
proaches the same level of activity as peripheral skin. It may: x0 C2 q! J! l  a7 P1 N& B
well be that absorption of testosterone is less when applied at$ Y; ~* Y! ]7 p+ y4 j- ^/ i8 N" H
an earlier age as suggested by lower serum levels in children9 e, K7 Y  [5 O% z% g& N% g
less than 10 years old. This fact may be explained by the, B) ~4 \9 x7 n/ N/ f. ^6 n
greater ability of phallic skin to convert testosterone to dihy-& t1 u6 `/ T8 z% Q
drotestosterone at this age. Conversely, serum levels in older# Q3 I( O# U( m; I, H# D0 J3 o
patients were higher, possibly because of decreased local
, ~" [8 ^  L) B667
0 F0 Z% |% G* D; q* G668 KLUGO AND CERNY. o3 M, j3 ]3 ?+ ^5 v
Pt. Age
1 R4 A# q. j0 [, \8 [(yrs.)
% |+ |1 g9 |: T0 pSerum Testosterone Phallus (cm.) Change Length/ g  s% p5 V7 K8 V, A3 y3 X
(ng./dl.) Girth x Length (%); {! a4 p7 M/ R7 c
4- k( S+ j% {  l* i
8! p  Q7 z* @; E$ Z
106 [! H3 G8 O  H/ j5 ]
128 _7 N. V3 ~: w9 T4 j
17
+ J4 d2 p' V" h0 R, XGonadotropin8 ^2 x/ b. I5 H
71.6 2.0 X 3 16.6; H' ~! a3 b5 _* Z/ @) u6 c' j& n- l
50.4 4.0 X 5.0 20.0* t& @. Z! T# Y# Q8 i
22.0 4.5 X 4.0 25.0- ^$ u+ o* z5 o; t" Y  V
84.6 4.0 X 4.5 11.1
! N0 t6 _' o: U) f85.9 4.5 X 5.5 9.0- f: A$ Z  U5 f. @+ I
Av. 14.3
  V5 ~1 \2 q- A, k) X46 d) ?2 x* C8 t6 }! @5 E4 f$ e
84 B/ p. w, a6 ^1 z8 I+ L
10
) ~0 w0 f- R* V4 {8 X. N12) |: ^3 p) Q; Z2 N
17
, B& E2 C: j9 U7 B" z$ v( |2 w4 bTopical testosterone
8 V; {3 Y5 F* x5 B3 t- E1 y34.6 4.5 X 6.5 85
! i' k# z4 I, g% Q& m) x/ ~8 N38.8 6.0 X 8.5 70* @5 I& O; Z" }! [8 q) L+ d: U
40.0 6.0 X 6.5 62.50 g6 m0 U4 U2 i( W
93.6 6.0 X 7.0 55.5
! o& @( A) ~: u) z* j! Y5 s9 k* S95.0 6.5 X 7.0 27.2
9 b! }, @" R7 \: k" N- w6 ~Av. 60.02 u: G* B  y  r  {. ^( x3 U
available testosterone. Again, emphasis should be placed on3 }) ]0 p5 j7 ]+ O- c2 D  u  r
early therapy when lower levels of testosterone appear to
8 r4 ~% m: {9 ~) s' Lprovide the best responses. The earlier therapy is instituted- x: V. ~2 |1 z  ~- z
the more likely there will be an excellent response with low' v# k& g: w1 x6 f' j5 `  S
serum levels. Response occurs throughout adolescence as
% G' y' {* C3 S+ G3 e6 Q9 \noted in nomograms of phallic growth. 7 The actual response
: }& `+ k* y6 G; N, W& k# tto a given serum level of testosterone is much greater at birth' z/ f4 d, v% Y) X0 M- ^0 Y
and gradually decreases as boys reach puberty. This is most
# A/ s3 f; P& ]  w$ I* y, slikely related to the conversion of testosterone to dihydrotes-" z: ~; B. ?+ T" j" S
tosterone and correlates well with the studies of testosterone3 F7 D0 p% b+ G3 f) ~: B5 E
conversion in foreskin at various ages.
* S# Q6 |  }0 ~+ E7 t) GThe question arises regarding early treatment as to whether' n8 |  @+ ^- [( ~' @, G" W
one might sacrifice ultimate potential growth as with acceler-
" x' `) i$ B7 \7 L' A; xated bone growth. The situation appears quite the reverse) V8 F( M* Q# n, X& K1 [1 ]
with phallic response. If the early growth period is not used
3 R9 o/ G) m2 n3 I% h, s) z/ J5 Dwhen 5a reductase activity is greatest then potential growth
. m- Q" D' Z, {8 J+ m; kmay be lost. We have not observed any regression of growth$ ?0 @" e) `3 ]) }! |; g
attained with topical or gonadotropin therapy. It may well9 ^5 v/ m3 i, q( ]2 s! V9 K2 D
be that some patients will show little or no response to any
4 h" Z- ]5 N0 z3 mform of therapy. This would suggest a defect in the ability to
/ W. E! e! F, [) Zconvert testosterone to dihydrotestosterone and indicate that9 z! y& D. J7 Y+ G; b  ?# \0 v
phallic and peripheral skin, and subcutaneous tissue should
* y' `" i- E- W- p: Lbe compared for 5a reductase activity.8 P! x% J+ A. C1 I7 h$ E
A, loop enlarges to measure penile girth in millimeters. B,8 f0 T2 c) P# @! S. x2 E1 u6 n5 u
example of penile girth computed easily and accurately.
9 X  E% J& j, T: H" a/ Uconversion of testosterone to dihydrotestosterone. It is in this
; b  {  l; T- T3 d+ N" Qolder group that others have noted high levels of serum
; y& |. \- {: P; d3 Jtestosterone with topical application. It would also appear
( `* E0 O+ |& G3 C( K4 b7 bthat phallic response during puberty is related directly to the7 u+ E) I& b- O  p
serum testosterone level. There also is other evidence of local' s" {3 v: c. _0 u9 R
response to testosterone with hair growth and with spermato-
- b! z% \+ C3 U6 E1 `; m' qgenesis. 5• 69 u) `* H. U: k& t
Administration of larger doses of gonadotropin or systemic
9 V. r1 C/ n& rtestosterone, as well as topical applications that produce
# Y  A8 y* R* `+ m6 l% c8 Phigher levels of serum testosterone (150 to 900 ng./dl.), will- G$ E( y/ S# o
also produce phallic growth but risks accelerated skeletal+ q5 S% P! {4 T
maturation even after stopping treatment. It would appear% i/ F# R7 O1 b: L! M, l) i
that this may be avoided by topical applications of testosterone. k/ ~5 t. }- a$ R% O$ ?1 J0 Q
and monitoring of serum testosterone. Even with this control
% C. E, G# G. }% S/ gthe duration of our therapy did not exceed 3 weeks at any
, X) U( K( R, f$ ?3 i" |& L( Utime. It is apparent that the prepuberal male subject may
' ?& _9 Q+ h6 g$ }6 O9 Csuffer accelerated bone growth with testosterone levels near
/ ~5 |- N: N) j( T: ?200 ng./dl. When skeletal maturation is complete the level of2 J0 Y  d/ r' s5 o
serum testosterone can be maintained in the 700 to 1,300 ng./
9 s! F% s# o. |9 a' B- D0 L, W6 Ddl. range to stimulate phallic growth and secondary sexual
: A/ y5 y6 E6 L9 H/ s7 e7 Xchanges. Therefore, after skeletal maturation parenteral tes-
+ B' @$ f; A7 q! G+ n; Ptosterone may be used to advantage. Before skeletal matura-
3 }8 g# X- {; w7 btion care must be taken to avoid maintaining levels of serum+ P5 z1 e) I" u* f+ i# m" Q3 z9 d
testosterone more than 100 ng./dl. Low-dose gonadotropin
8 L7 s1 d/ g8 t6 zdepends upon intrinsic testicular activity and may require
3 |9 _. b* e3 J( @* u8 c: Cprolonged administration for any response.
# T. O! d* P2 O$ ?Alternately, topical testosterone does not depend upon tes-
. M: z8 b& {6 N+ Q6 Y$ f. j  N$ r) oticular function and may provide a more constant level of1 M8 \# s! W9 E5 [
REFERENCES
! S& m/ w/ n" _1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
4 Q) D0 w; s8 F7 w& GR.: The local application of testosterone cream to the prepub-
' f  I* `7 {8 Z! Rertal phallus. J. Urol., 105: 905, 1971.4 b4 @- A- i6 ^) c- n, A% E1 z5 V$ r
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone. _' r; h, J% O: L0 {$ \6 L
treatment for micropenis during early childhood. J. Pediat.,! c1 W! h+ |% v5 Z4 d5 H5 i8 n4 m; `. ^
83: 247, 1973.
9 T# m# F6 _5 e. N$ d3 }3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-- t$ S  E5 D$ d+ u3 r7 T  @
one therapy for penile growth. Urology, 6: 708, 1975.# y7 c# z  @6 j5 |( X# h/ k
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone8 v) }: }9 j9 e2 m* z) M$ e' D
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by/ P! m3 b3 P7 E* o6 Y
skin slices of man. J. Clin. Invest., 48: 371, 1969.1 b! s$ t" R  R5 R6 q2 Z
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
, b! e6 n1 H" |  a2 }/ uby topical application of androgens. J.A.M.A., 191: 521, 1965.8 l& H( y1 c9 W* l2 p
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
# a- R5 h; ~) `9 W" v6 i* |androgenic effect of interstitial cell tumor of the testis. J.
9 \+ h, z7 x7 g8 A+ u9 X3 [Urol., 104: 774, 1970.
6 l4 c& \2 e# @' N" _' t2 Z7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
  n" O3 E) N! n8 q# n. ation in the male genitalia from birth to maturity. J. Urol., 48:
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